The majority of intraepithelial lymphocytes (IELs) that reside within the epithelia are fully differentiated CD8 effector memory T (TEM) cells. These lymphocytes acquire their effector phenotype and functional differentiation in response to antigens in peripheral lymphoid organs.1 Consequently, one of the major achievements of the immune memory process is the gradual seeding of nonlymphoid tissues with fully differentiated CD8 TEM cells selected for the antigens present in the immediate environment. Their strategic localization suggests a critical role for these antigen-experienced cells as first-line defenders, capable of providing early immunity when invading pathogens are probably most susceptible to immune control.

In agreement with this, a recent study by Jiang et al.2 showed that functionally differentiated skin-resident TEM cells generated protective immunity against cutaneous infections and reinfections that was far superior to that provided by circulating, self-renewing, central memory T (TCM) cells. These new findings join a growing body of evidence that preexisting, fully differentiated TEM cells at peripheral interfaces, where most pathogens first enter, form one of the most critical arms of protective cell-mediated immunity.3,4,5,6,7,8

The role of CD8 memory T cells in providing protection against infections by intracellular pathogens, such as viruses, bacteria, and protozoan parasites, has been well recognized, and major efforts have been made to provide vaccine-induced, pathogen-specific CD8 T-cell immunity.9 However, conventional vaccine strategies, which have been focused on the recall responses of TCM cells in secondary lymphoid tissues, have largely failed in inducing effective protective immunity, especially against pathogens such as HIV that are naturally transmitted across mucosal borders.10 This implies that the antigen-induced quantitative hallmark response of TCM cells, which is required for their effector differentiation before they can migrate to the site of infection and participate in the protective response, might develop too slowly to provide the early adaptive immunity that could prevent transmission and systemic dissemination of invading pathogens. By contrast, other recent reports5,7 showed that vaccine-induced mucosal CD8 TEM cells were able, in the absence of neutralizing antibody, to effectively block establishment of systemic infection after mucosal challenge with a highly pathogenic simian immunodeficiency virus, presumably by interfering with the initial viral replication. In addition to achieving early pathogen control, the rapid responses of TEM cells averted overt inflammatory responses that would impose a threat to the integrity of mucosal barriers.

Taken together, these new insights indicate that, to achieve effective vaccine-based protection, it will be important to establish close synergy between both a local qualitative TEM-cell component and a systemic quantitative TCM-cell component, with the former providing early preventive immunity at the site of infection and the latter serving as a second line of defense capable of clearing the pathogen in case the initial TEM-cell barrier is breached.

The new advances also imply that the aim of improved or new vaccination strategies must be not only the generation of antigen-specific TCM cells that can expand robustly upon rechallenge in secondary lymphoid tissues but also, equally important, the accumulation of preexisting, highly sensitive local TEM cells at the mucosal interfaces. Nevertheless, the functional hallmarks that distinguish the protective efficacy of the memory T-cell subsets suggest that distinct mechanisms might drive their explicit generation and long-term maintenance. In support of this, data have shown that local induction and optimal activation conditions—for example, in the presence of efficient innate stimulation and proinflammatory cytokines such as interleukin-12 or in response to high-avidity/-affinity stimulation—preferentially lead to the differentiation of protective TEM cells.4,8,11,12,13 By contrast, systemic memory differentiation under conditions that preclude full activation, such as in the presence of the suppressive cytokine interleukin-10, as was shown recently,14 interferes with effector differentiation and leads mainly to the accumulation of lymphoid TCM cells.14,15 In addition, we have previously shown that a unique survival mechanism—mediated by the activation-induced expression of CD8a homodimers (CD8aa), which function as T-cell-receptor repressors and counteract the coreceptor function of CD8ab,16—results in the rescue of memory precursor cells from activation-induced cell death.17 Induction of CD8aa is proportional to the signal strength of activation, thereby marking the highest-avidity/-affinity memory precursor cells with the highest level of CD8aa expression.8 Interestingly, we also found that CD8aa marked high-affinity/-avidity effector cells that were selectively preserved as mucosal memory precursor cells and that accumulated as TEM-cell IELs in the intestine.8 The data further showed that continuous selection pressure, enforced by the epithelium, enriched for the long-term survival of high-avidity/-affinity IELs, whereas less antigen-sensitive cells were constantly being eliminated from the pools of resident mucosal TEM cells.8

These new insights into protective immunity have revealed that perhaps one of the most important, although underappreciated, functions of memory T-cell differentiation is the selective seeding of the mucosal barriers with highly sensitive and fully differentiated antigen-experienced IELs, which function as effective sentinels and rapidly respond before the pathogen or the systemic immune system has a chance to jeopardize the integrity of these critical surfaces. Therefore, the efficacy of the new generation of vaccination strategies will depend greatly on the answer to the question “Got IELs”?