Introduction

One of the fundamental assets of the T-lymphocyte system, in addition to its capacity to circulate, is its capacity to undergo homeostatic changes in response to alterations of the internal environment. Whether the origin of these alterations is from outside or from inside, physical contact between cells and molecules of the immunological system on the one hand, and of the altered internal milieu on the other, are necessary to elicit activation signals that will ultimately result in qualitative and quantitative changes within the peripheral T-cell pool. The signalling events following the primary (e.g. TCR/MHC) and secondary (e.g. CD2/LFA-3, CD28/B7) interactions play key roles in the process of T-cell activation and function and have been well reviewed elsewhere.^{1, 2, 3, 4} Nevertheless, despite the fact that professional antigen-presenting cells (APC), such as dendritic cells, tissue macrophages, monocytes and activated B cells, can initiate an immunological response by primarily activating CD4⁺ T cells, accumulating evidence indicates that the alterations of the T-lymphocyte system in response to signals of the internal milieu result in phenotypic changes mostly affecting the CD8⁺ T-cell pool. The most conspicuous phenotypic changes under these situations are downmodulation of the CD3 chain and complete loss of CD28, which are counteracted by de novo expression of non-specific T-cell markers such as CD11b, CD56, CD57 and CD161. The molecular basis for, and physiological significance of, the increased tendency of CD8⁺ T cells to undergo shifts in response to alterations of the internal milieu is unclear. However, recent data indicate that non-haematopoietic cells, such as epithelial cells, are capable of activating CD8⁺ T cells. In turn, the activated CD8⁺ T cells may be involved in the regulation of basic physiological processes within the organ and/or tissue they populate. To elucidate the mechanisms involved in the activation of CD8⁺ T cells, loss of CD28 expression and the generation of differentiated CD8⁺CD28^– T cells with regulatory functions is of foremost importance. The purpose of this review is to bring up to date the certainties and uncertainties of this prevalent human CD8⁺ T-cell subset.

CD8⁺CD28^– T cells: From phenotype to function

Although CD28 provides a critical costimulus for T-cell activation,^{1, 2, 3, 4} a large fraction of human peripheral blood T cells lack CD28, which is due to the different expression of CD28 by the two major T-cell subsets. While in healthy humans CD28 is expressed by the majority of CD4⁺ T cells, the percentage of CD8⁺ T cells coexpressing CD28 is highly variable.^{5, 6, 7} Peripheral blood CD8⁺CD28^– T cells are enriched for large, granular lymphocytes (Figure 1), express high levels of LFA-1 and variable amounts of CD11b and CD57, a phenotype associated with memory/effector cells.^{5, 6, 7} Freshly isolated peripheral blood CD8⁺CD28^– T cells from healthy humans do not express markers of early (e.g. CD69) or chronic (e.g. HLA-DR) activation and proliferate poorly in response to conventional mitogenic stimulation in vitro.⁷ A CD4⁺ T-cell subset with similar phenotypic and functional characteristics also exists, at very low frequencies, in the peripheral blood of healthy humans.^{8, 9}

Figure 1.

Human CD8⁺CD28^– T cells are enriched for large, granular lymphocytes. Freshly collected human peripheral blood lymphocytes from a healthy blood donor were stained for CD8/CD28 and acquired in a FACScalibur according to forward and side scatter characteristics (FSC/SSC, left dot blot). After magnification, two electronic gates were created around small/agranular (gate 1) and large/granular (gate 2) lymphocytes. CD28 expression among (CD3⁺)CD8^bright T cells within each electronic gate is shown on the right dot blots. The percentage of (a) CD8⁺CD28⁺ and (b) CD8⁺CD28– T cells are indicated.

Full figure and legend (41K)

Although the existence of a pool of circulating CD8⁺CD28^– T cells in humans has been known to exist for more than 15 years, specific interest in this CD8⁺ T-cell subset arose after finding increased numbers during infections.^{10, 11, 12, 13, 14} CD8⁺CD28^– T cells were first described as suppressors of B- and T-cell function, but subsequent studies have shown that CD8⁺ T cells bearing the CD28^– phenotype (CD11b⁺ and/or CD57⁺) may also mediate cytotoxicity.^{15, 16, 17, 18} Studies with freshly isolated peripheral blood lymphocytes demonstrated that CD8⁺CD11b⁺ T lymphocytes contain cells capable of suppressing proliferation and IgG synthesis of B cells, and cells that express the IL-2 receptor chain (CD8⁺CD122⁺ T cells) and develop into cytotoxic T lympho-cytes (CTL) after culturing with IL-2.^{18, 19, 20, 21} Importantly, IL-2-induced CD8⁺ T-cell proliferation results in CD11b loss and the generation of CD8⁺CD28^–CD11b^– T cells,²¹ a non-cytotoxic subset expanded in the blood of HIV-1-infected patients.²² Recent work by Suciu-Foca and coworkers has disclosed some of the molecular mechanisms that account for the suppressor activity of CD8⁺CD28^– T cells.^{23, 24, 25} By inhibiting the nuclear factor kappa B (NF-B) mediated transcription of the CD86 gene, CD8⁺CD28^– T cells hamper the ability of classical APC to elicit CD28-driven CD4⁺ T activation and proliferation, a suppressor activity that is MHC-class I-restricted.^{23, 24, 25}

These data clearly indicate that CD8⁺CD28^– T cells are a heterogeneous subset that contains both memory and effector cells.²⁶ The most established view, however, considers CD8⁺CD28^– T cells as terminally differentiated or end-stage CTL; a belief based on phenotypic and functional studies. First, CD8⁺CD28^– T cells express CD11b, a member of the 2-integrin family expressed by monocytes, neutrophils and natural killer (NK) cells,²⁷ which is considered to be a marker of CD8⁺ cytotoxic T-cell activation in response to viral infection in mice.^{28, 29} Yet, together with LFA-1, another 2-integrin, CD11b is believed to play an important role in extravasation of lymphocytes after adhesion to the endothelium via intercellular adhesion molecule-1 (ICAM-1).^{27, 30} In addition, along with peripheral blood CD8⁺ T cells, CD11b is expressed by a significant fraction of CD3⁺ T cells in the liver and spleen of healthy subjects.³¹ Recent studies suggest that the acquisition of CD11b represents an early event during human CD8⁺ T-cell differentiation, which may allow extravasation to peripheral tissues.³² Second, CD8⁺CD28^– T cells express CD57, a molecule containing the epitope human natural killer cell carbohydrate antigen-1 (HNK-1), which is present on human NK, CD4⁺ and CD8⁺ T cells.^{33, 34} CD57, in a manner analogous to CD11b, is a marker associated with CTL effector function due to its increased expression among CD8⁺ T cells during immune responses to viral infections.^{35, 36, 37, 38} However, the HNK-1 epitope is also present on glycolipids and glycoproteins expressed in the central nervous system (e.g. MOG and NCAM) and involved in cell–cell interactions.³⁹ In this context it is important to note that CD8⁺ T cells expressing CD57, but not CD11b, are present at low levels in normal bone marrow.^{40, 41} Finally, CD8⁺CD28^– T cells are enriched for large granular lymphocytes that contain perforin,^{7, 26} a protein involved in target cell apoptosis.⁴² Thus, these data reveal that CD8⁺CD28^– T cells are a multifaceted population capable of performing many functions, with cytotoxicity the most extensively studied. Indeed, a recent study on circulating CD8⁺CD28^– T cells has shown that CTL effector function correlates with the expression of CD56,⁴³ a typical NK marker also containing the HNK-1 epitope.³⁹

Although the loss of CD28 and gain of CD11b and/or CD57 by peripheral blood CD8⁺ T cells is the result of a differentiation process that generates cells with cytotoxic potential, to consider CD8⁺CD28^– T cells as end-stage CTL effectors constrains the study of other functions that this CD8⁺ T-cell subset may perform. Thus, the increase in CD8⁺CD28^– T cells in peripheral blood could be the result of a viral infection,^{10, 11, 12, 13, 44, 45, 46, 47, 48, 49} but may also be a response to alterations of the internal environment,^{50, 51, 52} or even of homeostatic changes within the peripheral T-lymphocyte system itself. In addition, the CTL effector function detected among expanded CD8⁺CD28^– T cells during viral infection^{43, 44, 45} has been difficult to detect by some authors,^{47, 48, 49} unless the bulk of the CD8⁺ T cells were first incubated with IL-2, a cytokine that upregulates CD3 and restores their cytotoxic potential.⁴⁸ The recently developed peptide-HLA tetramer technology has allowed researchers to isolate and study in more detail peptide-specific CD8⁺ T cells from peripheral blood during primary and secondary viral infections.⁵³ Surprisingly, these studies have shown that tetramer-specific CD8⁺ T cells are a complex population, which in most cases show impaired cytotoxicity activity.^{54, 55, 56, 57, 58, 59} Although the CD8⁺CD28^– T-cell phenotype has been associated with terminal differentiation, unresponsiveness and cytotoxicity it is important to note that increased numbers of circulating CD8⁺CD28^– T cells in a number of disease conditions and situations have been reported. As shown in Table 1, despite being the most studied, viral infections are only one among the many possible situations that could lead to the generation of CD8⁺CD28^– T cells in humans.

Table 1 - Human conditions and disorders associated with an increase in the percentage and/or number of peripheral blood CD8⁺CD28^– T cells (defined either as CD28^–, CD11b⁺or CD57⁺).

Full table

Signals and pathways for CD28 downmodulation

T-lymphocyte activation in vitro and in vivo results in increased internalization and degradation of components of the TCR/CD3 complex, namely the CD3 chain, and this results in the downmodulation of cell surface CD3.⁶⁰ T-cell activation by MHC-peptide complexes, B7-expressing cells or mitogens, such as phytohaemagglutinin, also results in CD28 downmodulation by peripheral blood T cells.^{61, 62, 63} In contrast to CD3, modulation of cell surface CD28 initiated after TCR-engagement results in the complete loss of CD28 after several cycles of cell division in the presence of -chain receptor signalling cytokines such as IL-2, IL-7 and IL-15.^{64, 65, 66, 67} Hence, CD28 downmodulation initiated after TCR triggering appears to be an irreversible process that is modulated by various factors and cytokines and leads to the generation of CD8⁺CD28^– T cells in humans. In an elegant study using CD8⁺ T cells, Fiorentini et al. showed that after prolonged in vitro stimulation in the presence of IL-2, CD8⁺CD28⁺ T cells showed a gradual decrease in CD28 cell surface and mRNA levels and matured into a stable CD8⁺CD28^– phenotype.⁶⁶ Similar results were obtained by Labalette et al. which, in addition, showed that IL-4 inhibited this process.⁶⁸ Thus, loss of CD28 is a hallmark of T cells that have undergone many cycles of cell division. Indeed, loss of telomeric DNA resulting from cell division^{69, 70} is observed in CD8⁺CD28^– T cells from healthy and diseased subjects,^{71, 72} an indication of their higher replicative past when compared with their CD8⁺CD28⁺ T-cell precursors. Telomeric shortening is only evident among CD8⁺ T cells that have completely lost CD28 expression,^{73, 74, 75} thus, suggesting a link between CD28 downmodulation and telomerase activity. Two recent studies have revealed that telomere shortening in peripheral blood lymphocytes also takes place during the first years of life,^{76, 77} indicating that T cells undergo a high turnover during early childhood, which is a time when internal changes (e.g. organ and tissue remodelling) are still taking place.

To date, CD28 is the only T-cell surface molecule, which has been described, that undergoes complete downmodulation, a process that is more apparent on CD8⁺ T cells. Considering the phenotypic changes associated with CD28 downmodulation,³⁸ identification and characterization of the activation signals and factors that regulate CD28 is of great importance. In this context, recent studies by Goronzy and coworkers have shown that the differences in CD28 expression between CD4⁺ and CD8⁺ T cells correlate with differences in nuclear protein-binding activities to two motifs, and , located within the CD28 promoter.⁷⁸ In vitro activation via the TCR/CD3 complex correlates with loss of /-binding activities both in CD4⁺ and CD8⁺ T cells and partial CD28 downmodulation. On the contrary, repeated activation and long-term culture in the presence of IL-2 results in loss of - but not -binding activities and correlates with a marked modulation of CD28 expression solely on CD8⁺ T cells, a pattern of expression that mirrors what happens in vivo.⁷⁸ It is important to note that freshly isolated CD4⁺CD28^– and CD8⁺CD28^– T cells lack /-binding activities. Further characterization of these lymphoid factors may turn out to be of paramount importance in elucidating the nature of the environmental signals and factors that lead to the loss of CD28 by CD8⁺ T cells.

Despite the recent advances in our understanding of how CD28 expression is regulated, it is difficult to determine which cells provide the original stimulus and the context in which CD8⁺CD28^– T cells develop. Still, the well-known MHC-restriction of CD8⁺ T cells argues in favour of a predominance of MHC-class I⁺ versus MHC-class II⁺ cells in displaying alterations of the internal environment. Furthermore, in the case of continuous encountering with the MHC-class I⁺ cells, this prevalence would have an immediate output: the accumulation within the peripheral CD8⁺ T-cell pool of CD28^– T cells carrying similar TCR specificities. The reported oligoclonality of CD8⁺(CD57⁺)CD28^– cells both in health and in disease is in accordance with this scenario.^{79, 80, 81, 82, 83} The fact that CD8⁺CD28^– T cells are oligoclonal and have short telomeres,^{71, 83} together with the existence of identical clones in CD8⁺CD28⁺ and CD8⁺CD28^– &Tgr; cells⁸⁴ stresses the MHC-class I driven mechanism. CD8⁺CD28^– T-cell oligoclonality may also suggest that a restricted pool of MHC-class I/peptide structures account for most of the CD8⁺CD28^– T-cell expansions. Alternatively, conserved structures in physical association or combination with MHC-class I molecules may also be involved. Finally, the possible role played by non-classical MHC-class I molecules in driving the CD28⁺ to CD28^– transition cannot be ruled out. In any case, and contrary to current beliefs, the preferential modulation of CD28 observed in CD8⁺ T cells may be advantageous rather than deleterious.

CD8⁺CD28^– T-cell origin and function: Clues from health and disease

The presence of CD8⁺CD28^– &Tgr; cells in peripheral blood of healthy individuals is a common event. In some subjects CD28^– T cells may represent more than half of the peripheral CD8⁺ T-cell pool.^{6, 7} Among the factors implicated in the generation of peripheral blood CD8⁺CD28^– T cells in healthy subjects, age is the most important and most studied Table 1). Posnett et al. first described expanded pools of oligoclonal CD28^– T cells among freshly isolated peripheral blood CD8⁺ T cells of aged humans.⁷⁹ In another study, Effros et al. reported that centenarians, and long-term T-cell cultures, showed a decline in CD28⁺ T cells.⁶⁴ Herein after, Fagnoni et al. studying a group of healthy people that included centenarians showed a direct correlation between age and the numbers of peripheral blood CD8⁺CD28^– T cells.⁸⁵ Although some groups have reported an increase in CD8⁺CD28^– T cells with age;^{31, 85,86} others have not been able to find such a correlation.^{87, 88, 89} The basis for these discrepancies may result from the study of cohorts with different genetic backgrounds or from the unforeseen influence of environmental factors⁸⁹ on the percentage of CD8⁺ T cells. The only reliable correlation found with age is a decline in (CD8⁺)CD28⁺ T cells.^{31, 64,85, 86, 87, 88, 89, 90}

The reduction in peripheral blood CD8⁺CD28⁺ T cells that takes place with age, along with the accumulation of a pool of unresponsive CD8⁺CD28^– T cells with shortened telomeres, has led to the concept of replicative senescence.^{91, 92, 93, 94} However, the weak responsiveness of CD8⁺CD28^– T cells to mitogenic stimulation rather than being a feature of their senescence may be an indication that they are prepared to receive a different stimulus. The recent evidence that telomerase activity is intact in T cells from aged people reinforces this assumption.⁹⁵ Thus, study of costimulatory molecules expressed on activated/memory T cells, such as ICOS, PD-1, LFA-1, 4-1BB,^{96, 97, 98} may give important clues to the functional status of CD8⁺CD28^– T cells. In this context, special attention should be given to de novo receptors expressed by CD8⁺CD28^– T cells, such as the family of natural killer receptors.^{88, 99}

Studies of diseases in which increased numbers of CD8⁺CD28^– T cells have been reported may provide insights into the mechanisms that drive the emergence of these CD8⁺ T cells in peripheral blood and into their physiological function Table 1). In haemochromatosis (HFE), a genetic disorder characterized by an inappropriately high iron absorption in the small intestine and its subsequent accumulation in parenchymal cells of the liver, pancreas and other organs, increased numbers of CD8⁺CD28^– T cells are a hallmark of the disease.⁸⁷ Interestingly, follow-up studies showed that CD8⁺CD28^– T-cell expansions persist over time and afford protection from development of hepatocellular carcinoma.^{87, 100} Although HFE, the gene product responsible for the disease, is a non-classical MHC-class I molecule,^{101, 102} there is no formal proof for its direct involvement in the activation of CD8⁺ T cells. However, the presence of activated and oligoclonal CD8⁺ T cells in these patients^{87, 103} is an indication of their continuous priming under an iron-overloaded environment. Furthermore, increased numbers of CD8⁺CD28^– T cells, containing expansions of oligoclonal T cells, have also been reported in the peripheral blood of heavy alcohol drinkers without liver disease.⁸⁹ Interestingly, high CD8⁺CD28^– T-cell numbers were associated with low levels of liver injury. These data are in accordance with previous studies in heavy alcohol drinkers without liver disease, which showed that CD8⁺ T cells have a typical profile of activated/memory cells, such as expression of CD57, CD45RO and HLA-DR.^{104, 105, 106} Together with the data from haemochromatosis patients these results suggest that CD8⁺CD28^– T cells may play a protective regulatory role under tissue injury caused either by ethanol or iron, and point to an epithelial-driven CD8⁺CD28^– T-cell generation. Through the production of reactive oxygen species iron and ethanol mediate protein damage and lipid peroxidation in parenchymal hepatocytes and result in epithelial cell injury.^{107, 108, 109, 110, 111} From an immunological point of view the stressed and/or injured epithelial cells may modulate the expression of molecules involved, directly or indirectly, in signalling to either resident or passenger CD8⁺ T lymphocytes¹¹² (see next section). Repeated CD8⁺ T-cell activation in the presence of chain signalling cytokines may lead to the generation of a progeny of CD8⁺CD28^– T cells with protective regulatory functions as discussed elsewhere.¹¹³

Increased numbers of peripheral blood CD8⁺CD28^– T cells have also been reported in chronic diseases (e.g. Crohn's disease, rheumatoid arthritis, Felty's syndrome, systemic lupus erythromatosus and Wegener's granulomatosis),^{114, 115, 116, 117, 118, 119} in haemophilic and haemodialysis patients,^{120, 121} and in patients with haematological tumours and immuno-deficiency^{122, 123, 124, 125, 126} (see Table 1). In some of these disease conditions increased numbers of CD8⁺CD28^– T cells are concomitant with chronic stimulation of CD4⁺ T cells. For example, in rheumatoid arthritis the increased number of circulating CD8⁺CD28^– T cells is paralleled by an increase in oligoclonal CD4⁺CD28^– T cells.^{127, 128} The CD4⁺CD28^– T-cell subset is a rare human T-cell subset characterized by autoreactivity and resistance to apoptosis,^{8, 9,128, 129, 130} which may preferentially originate in the context of certain HLA-DR alleles.¹³¹ As mentioned previously, the possibility that increased numbers of circulating CD8⁺CD28^– T cells in these diseases may result in part from homeostatic changes within the peripheral T-cell pool cannot be ruled out.

Longitudinal studies of peripheral T-cell populations in health and in disease have indeed unveiled the existence of a close relationship between CD8⁺CD28^– T-cell development and CD4⁺ and CD8⁺ T-cell numbers in peripheral blood. In other words, it is very likely that a variable fraction of the circulating pool of CD8⁺CD28^– T cells may, under certain circumstances, arise without the need of TCR triggering. First, human CD4⁺ T-cell lymphopenia due to Lck deficiency results in the replenishment of the peripheral T-cell pool with CD8⁺CD28^– T cells.¹³² Second, low CD4/CD8 T-cell ratios anticipate high percentages of CD8⁺CD28^– T cells in peripheral blood regardless of age.^{87, 89} Third, the progressive loss of CD4⁺ T cells, and naive CD8⁺ T cells observed in HIV-infected subjects is counteracted by an increase in effector/memory CD8⁺(CD28^–) T cells,^{133, 134, 135} an increase also observed in centenarians in which reductions in naive CD8⁺ T cells take place.¹³⁶ In all, these data suggest that CD8⁺CD28^– T-cell development is constrained by the size of the peripheral CD8⁺ T-cell compartment, in relation to the CD4⁺, and by the number of naive CD8⁺ T cells within this compartment. This constraint is in accord with the genetic control of the peripheral CD4/CD8 T-cell ratio,^{137, 138} its constancy over time in humans^{139, 140} and the close relationship observed between both pools in reconstituted mice.¹⁴¹ In this scenario, CD8⁺ CD28^– T cells will expand when a decrease in total CD4⁺ T cells, or naive CD8⁺ T cells, takes place within the peripheral T-cell compartment, regardless of the origin and nature of the cause. This increase could be modulated in a positive or a negative manner by the presence or absence, respectively, of signalling cytokines both in humans¹⁴² and in mice,^{143, 144, 145} or by additional stimuli such as viral infection, iron overload or ethanol consumption. This setting fits well with current data indicating that CD8⁺CD28^– T cells divide faster and live longer than CD8⁺CD28⁺ and CD4⁺ T cells, features likely to be related to a shorter cell division cycle, a higher resistance to apoptosis and a different response to regulatory cytokines.^{65, 66, 67, 68, 146, 147}

Are epithelial cells involved in the generation and/or maintenance of CD8⁺CD28^– T cells?

Cells expressing high levels of MHC-class II molecules, such as dendritic cells, activated monocytes and B cells and tissue macrophages, are considered the classical APC. However, evidence accumulated during the past decade indicates that intestinal epithelial cells (iEC) are also capable of activating T cells.¹⁴⁸ Early in vitro studies demonstrated that ex vivo iEC from rats and humans were capable of activating peripheral blood T cells. Paradoxically, the T cells driven into proliferation by iEC were CD8⁺ T cells.^{149, 150} It is now known that both ex vivo iEC and iEC tumour cell lines are capable of generating CD8⁺CD28^– T cells in vitro, although using different mechanisms.^{150, 151} While CD8⁺CD28^– T-cell generation by ex vivo iEC involves activation and proliferation of CD8⁺ T cells, generation by iEC lines entails death of CD4⁺CD28⁺ and CD8⁺CD28⁺ T cells, thus strengthening the resistance of CD8⁺CD28^– T cells to apoptosis.¹⁵¹

Evidence gathered during the last few years suggests that CD1d and gp180 are involved in the activation of human CD8⁺ T cells.^{152, 153, 154, 155} CD1d is a non-classical MHC-class I molecule that is expressed in iEC, parenchymal hepatocytes and stromal cells.^{156, 157} Dendritic cells, monocytes, B cells and activated T cells express low levels of CD1d.^{158, 159, 160} In contrast, gp180 is a heavy glycosylated protein that is expressed by the intestinal, thymic and airway epithelium, and in trophoblasts.¹⁶¹ While CD1d is thought to interact with the TCR of the CD8⁺ T cell, gp180 interacts with the CD8 molecule and activates its associated tyrosine kinase Lck.^{152, 153} The CD8/gp180 interaction plays an important role not only in Lck activation, but also in the adhesion of CD8⁺ T cells to iEC.¹⁵¹ In this scenario, MHC-class II molecules appear to modulate the epithelial-driven CD8⁺ T-cell activation.¹⁵² The capability of iEC to activate human CD8⁺ T cells in vitro has also been observed with hepatic parenchymal cells,^{162, 163} airway epithelial cells,¹⁶⁴ endothelial cells¹⁶⁵ and fibroblasts.¹⁶⁶ Whether the CD1d/gp180 pair is involved and whether the proliferating CD8⁺ T cells become CD28^– is unknown, but cocultures of epithelial cell lines from different origins with peripheral blood T cells results in accumulation of CD8⁺CD28^– T cells.¹⁵¹

The generation of CD8⁺CD28^– T cells by epithelial cells could be envisaged as the result of the existence of communication between epithelial tissues and CD8⁺ T cells. This cross-talk constitutes a unique feature that may help to understand the phenotypic changes that take place within the peripheral T-lymphocyte system under a variety of situations Table 1). Thus, altered expression of CD1d by epithelial cells has been implicated in the pathogenesis of certain autoimmune disorders.^{170, 171, 172} Other studies, however, have suggested that faulty expression of gp180, rather than CD1d overexpression, may be responsible for the pathogenesis of certain inflammatory diseases.¹⁷³ On the contrary, when expressed by dendritic cells CD1d seems to preferentially activate CD4⁺ T cells and CD4^–CD8^– T cells bearing a conserved V chain.^{174, 175, 176} The potential of human CD1d to interact and activate opposite T-cell subsets may reflect presentation of different tissue-specific ligands, as shown in mice,¹⁷⁷ or a different physical association with conserved structures. In this context, CD1d has three distinctive features: (i) a hydrophobic binding groove that binds lipid compounds instead of classical peptides, in mouse CD1d1;^{178, 179} (ii) the presence of the YQGV motif in its cytoplasmic tail, a tyrosine-based internalization signal that targets the molecule to endosomal compartments;¹⁸⁰ and (iii) the capability to be expressed in the cell surface in a 2m-independent manner.^{181, 182} Nevertheless, even though CD1d is considered to be an important signalling molecule involved in the activation of distinct subsets of T cells,^{148, 161, 167, 168, 169, 174, 175, 176} it must be noted that cell surface expression of CD1d by untransfected human cells is very weak or absent, and is mainly cytoplasmic. This pattern of expression does not meet the classical requirements for an antigen-presenting molecule. Therefore, human CD1d may hold a specialized biological function that may be intracellular rather than extracellular (for a recent review of CD1d see Joyce¹⁸³).

Molecules having the MHC-fold, aside from CD1d, alone or in combination with conserved monomorphic structures and/or oxidatively modified proteins are candidate molecules whose expression on epithelial cells may allow a preferential CD8⁺ T-cell activation. Human MICA and MICB molecules (for MHC class I-chain related molecules) are expressed on the cell surface of stressed iEC and fibroblasts, and have the capability to activate CD8⁺ T cells.^{184, 185, 186} MICA is also expressed by human keratinocytes, endothelial cells and monocytes and seems to be expressed in the cell surface in a 2m-independent manner.¹⁸⁷ Although detailed studies of MICA and MICB expression in the conditions described in Table 1 have not been reported, it is anticipated that their expression, along with the expression of other signalling molecules, could be altered. In this context, increased expression of MHC-class I and ICAM-1 on hepatocytes of patients with haemochromatosis has been reported.¹¹² By analogy with studies in humans and mice,^{188, 189, 190, 191, 192, 193} altered expression of conserved molecules and molecules with the MHC-class I fold by epithelial cells under stressed conditions, such as during iron overload, may activate passenger and/or resident CD8⁺ T cells and generate a pool of CD8⁺CD28^– T cells that may act on the injured epithelial cell immediately or after recirculation. The cytokines and factors secreted may directly or indirectly regulate stress/injury and restore normal hepatic function. Although speculative at present, this scenario is not unlikely. Clinical and experimental data accumulated during the past 10 years have established the impact that low numbers of CD8⁺ T cells, both in peripheral blood and in the liver, have in the clinical setting of haemochromatosis.^{87, 100,140, 194, 195, 196} Studies of iron-rich body fluids, such as breast milk and the synovial fluid of rheumatoid arthritis patients^{197, 198} and of a model of hepatic injury¹⁹⁹ appear to support the assumption that CD8⁺CD28^– T cells play a protective role under stressed conditions and thus regulate epithelial physiology.

The majority of T cells populating epithelial tissues in humans (e.g. small intestine and liver parenchyma) are, like CD8⁺CD28^– T lymphocytes, phenotypically and functionally memory CD8⁺ T cells.^{31, 200, 201, 202, 203, 204, 205} Recent work by O'Farrelly and collaborators^{203, 204} has shown that a large fraction of human hepatic CD8⁺ T cells express activating and inhibitory NK receptors.²⁰⁶ These CD8⁺ T cells, called NKT cells, are also present in peripheral blood and are characterized by a lack of CD28 expression.^{43, 88, 207, 208} Although evidence for the expression of NK receptors by human intestinal intraepithelial lymphocytes (iIEL) is absent, a recent study showed that BY55, a glycosylphosphatidylinositol-linked protein, is expressed by both circulating CD8⁺CD28^– T cells and iIEL.²⁰⁹ First described in circulating NK cells, BY55 is expressed by cord blood and bone marrow CD8⁺ T cells, and in a large fraction of circulating CD8⁺ T cells in HIV patients.^{210, 211, 212} Therefore, this molecule links the circulating CD8⁺CD28^– T-cell pool and the mucosal CD8⁺ T-cell pool, which is also CD28^–.^{202, 213} In addition, both iIEL and hepatic NK CD8⁺ T cells lack cytotoxic activity, but gain cytotoxicity after culture in IL-2,^{204, 214,215} a feature also shared by CD8⁺CD28^– T cells.¹⁹ These phenotypic and functional similarities suggest that circulating CD8⁺CD28^– T cells may originate from CD8⁺CD28⁺ T-cell precursors that have acquired typical NK receptors during the differentiation process in epithelial tissues, thus, becoming NKT cells, as observed in mice.^{216, 217} It is important to note that NK receptors have also been described in circulating CD4⁺CD28^– T cells from rheumatoid arthritis patients, thus, indicating that induction/acquisition of NK receptors is linked to the differentiation process of the T cell.^{218, 219, 220} The likelihood that thymus- and/or bone marrow-derived CD8⁺ T cells, in the context of signals provided by environments such as the liver parenchyma or the intestine, differentiate, lose expression of CD28, transcribe and express cell surface NK receptors, such as CD161,²²¹ is an intriguing, but as yet, unexplored question.

Conclusions and future prospects

Studies in mice have shown that the maintenance of naive and memory CD8⁺ T cells in the periphery requires TCR–MHC interactions as well as cytokines and growth factors.²²² Although similar studies in humans are unfeasible, the negative impact of the absence of MHC-class I molecules or cytokine receptors, such as the chain, on peripheral T-cell homeostasis is well known.^{223, 224} Nevertheless, the nature of the MHC-class I⁺ cells that interact with CD8⁺ T cells in the peripheral tissues and organs and assure their survival is uncertain. Likely candidates are epithelial cells of the intestine and liver, two peripheral tissues usually populated by CD8⁺ T cells. Other organs and tissues, such as bone marrow, can also play an important role. By communicating with epithelial cells, circulating CD8⁺ T cells could secure not only their own survival but participate in the regulation of basic biological processes, from modulation of epithelial physiology^{199, 225, 226, 227, 228, 229, 230} and removal of apoptotic cells²³¹ to the regulation of local cell homeostasis.^{232, 233}

The primary signals delivered by epithelial tissues to CD8⁺ T cells can only be envisaged within the context of the cytokines produced in situ;^{234, 235, 236, 237} the nutrients for which CD8⁺ T cells compete,²²² soluble factors and receptors influencing T-cell function and receptivity,^{238, 239} and novel modulators of T-cell survival.²⁴⁰ Together with the signals delivered when the T lymphocyte has changed to the CD28^– phenotype, including those provided by engagement of NK receptors such as NKG2D via MICA,^{241, 242, 243} this myriad of environmental signals is likely to shape the peripheral T-lymphocyte system. Classical and non-classical MHC-class I molecules, together with the variety of the NK receptors that recognize those molecules, are thus central to T-lymphocyte homeostasis, namely of the CD8⁺ T-cell pool.²⁴⁴ These signals are expected to be delivered in normal conditions (e.g. during epithelial cell renewal) and in a number of situations during degeneration (e.g. senescence), injury (e.g. excess of iron and alcohol, viral infection) or modification (e.g. organ transplantation) of the internal environment. In these latter situations, however, a hastened generation of CD8⁺CD28^– T cells would take place. Given their functional heterogeneity and properties, CD8⁺CD28^– T cells are better positioned than other T-cell subsets to counteract these environmental changes. This prevalent human CD8⁺ T-cell subset, contrary to the current belief, may encompass highly specialized T cells with the capability to control and regulate tissue remodelling and repair within the microenvironment they populate on a day-to-day basis.

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Acknowledgements

I thank EMP Cardoso for invaluable suggestions and help during the writing of this manuscript, G Porto and M Santos for helpful discussions, AM Carmo for his unwavering belief in the immune system and AM Fonseca for providing the data for Figure 1. Last, but not least, I want to thank M de Sousa for her continuous support and for teaching me to look at the immunological system in a different way. Some of the work described in this review was supported by the Portuguese Science Funding Agency (FCT) and by the American Portuguese Biomedical Research Fund (APBRF). Regretfully, and due to space constraints, some original work was not referenced.