Unconventional T cells are a diverse and underappreciated group of relatively rare lymphocytes that are distinct from conventional CD4+ and CD8+ T cells, and that mainly recognize antigens in the absence of classical restriction through the major histocompatibility complex (MHC). These non-MHC-restricted T cells include mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, γδ T cells and other, often poorly defined, subsets. Depending on the physiological context, unconventional T cells may assume either protective or pathogenic roles in a range of inflammatory and autoimmune responses in the kidney. Accordingly, experimental models and clinical studies have revealed that certain unconventional T cells are potential therapeutic targets, as well as prognostic and diagnostic biomarkers. The responsiveness of human Vγ9Vδ2 T cells and MAIT cells to many microbial pathogens, for example, has implications for early diagnosis, risk stratification and targeted treatment of peritoneal dialysis-related peritonitis. The expansion of non-Vγ9Vδ2 γδ T cells during cytomegalovirus infection and their contribution to viral clearance suggest that these cells can be harnessed for immune monitoring and adoptive immunotherapy in kidney transplant recipients. In addition, populations of NKT, MAIT or γδ T cells are involved in the immunopathology of IgA nephropathy and in models of glomerulonephritis, ischaemia–reperfusion injury and kidney transplantation.
Unconventional T cells, such as γδ T cells, mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells, are distinct from classical CD4+ and CD8+ T cells and can have either protective or pathogenic roles in a range of inflammatory and autoimmune conditions related to acute and chronic kidney disease.
Vγ9Vδ2 T cells and MAIT cells respond to metabolites shared by a wide range of microbial pathogens, which may have implications for early diagnosis, risk stratification and targeted treatment of peritoneal dialysis-related peritonitis.
Non-Vγ9Vδ2 γδ T cells expand during cytomegalovirus (CMV) infection in kidney transplant recipients and contribute to viral clearance, which suggests that they can be harnessed for immune monitoring and for adoptive immunotherapy in refractory CMV infections.
IgA nephropathy is accompanied by oligoclonal expansion of γδ T cells in blood and the kidneys; this expansion correlates with disease progression and may contribute to immunopathology.
In murine models of glomerulonephritis, kidney γδ T cells are an important source of IL-17A, which is necessary for the recruitment of macrophages, neutrophils and T cells, and contributes to the development of kidney fibrosis.
Murine type I and type II NKT cells have opposite roles in ischaemia–reperfusion injury and may be relevant for allograft tolerance, as well as kidney protection in lupus nephritis or crescentic glomerulonephritis.
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The authors apologize to all colleagues in the field whose work was not cited owing to space limitations or unintended oversight. H.K. and L.C. were supported by Fondation pour la Recherche Médicale, Fondation du Rein and Fondation Bordeaux Université; M.E. was supported by the Medical Research Council, Kidney Research UK, the National Institute for Health Research and the Welsh European Funding Office’s Accelerate programme. The authors thank the members of their research teams and J. McLaren for critical comments on the manuscript before submission. H.K. and L.C. are deeply grateful to J. Déchanet-Merville and P. Merville for their thoughtful advice, mentoring and unwavering support.
The authors declare no competing interests.
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- Memory T cells
Long-lived antigen-specific T cells that remain in the body after the initial immune response has resolved and confer protection against a subsequent challenge with the same stimulus; effector memory T cells and tissue-resident memory T cells mount rapid recall responses at local sites, whereas central memory T cells patrol secondary lymphoid tissues.
- Adaptive immunity
Selective clonal expansion of individual T and B cells that are specific for non-self (for example, microbes, viruses or allergens) or self-antigens (autoimmunity or tumour antigens) and mount highly antigen-specific cellular and/or antibody responses. The expansion and differentiation of these antigen-specific cells increases the speed and efficiency of future memory responses to the same antigen.
- TCR repertoires
Summary of unique genetic rearrangements of the T cell receptor (TCR) in each T cell within an anatomical or functional compartment, which for classical T cells are typically polyclonal and ‘private’, whereas unconventional T cells are often oligoclonal and can carry invariant, ‘public’ TCR sequences shared between people.
(CMV). A virus that causes an infection that is almost asymptomatic in immunocompetent individuals but is associated with considerable morbidity and mortality in immunocompromised individuals; despite prevention strategies based on the use of antivirals, CMV-seronegative recipients who receive an organ from CMV-seropositive donors have the highest risk (20%) of developing CMV disease.
- Innate immunity
Nonspecific defence mechanism that is deployed within hours of encountering non-self structures (for example, a pathogen or a foreign object) or danger signals (triggered, for example, by tissue injury or stress); mediated by innate immune cells such as natural killer cells, mast cells, granulocytes (eosinophils, basophils or neutrophils), monocytes, macrophages and dendritic cells.
- Antigen presentation
Cellular process whereby antigenic epitopes are displayed on the surface of a cell for recognition by the T cell receptor (TCR) of a neighbouring T cell, typically as short peptides in the context of major histocompatibility complex (MHC) class I and class II molecules in the case of classical CD8+ and CD4+ T cells, respectively, or as non-peptide antigens in association with MHC-related molecules such as CD1 or MR1 in the case of unconventional T cells.
- Antibody-dependent cellular cytotoxicity
(ADCC). Immune mechanism through which effector cells carrying receptors for the crystallizable fragment (Fc) region of antibodies can recognize and lyse antibody-coated (that is, opsonized) target cells.
- Ischaemia–reperfusion injury
(IRI). Tissue damage that occurs after a period of oxygen deprivation due to ischaemia (that is, disrupted blood supply), which can be caused by sepsis, thrombosis, organ transplantation or trauma, and leads to inflammation, oxidative stress and necrosis following restoration of the normal blood supply.
- IgA nephropathy
The most prevalent form of glomerulonephritis in the world and a common cause of kidney failure; it seems to be a systemic disease in which the kidneys are the targets of galactose-deficient IgA1, which stimulates mesangial cells to proliferate, secrete pro-inflammatory and profibrotic cytokines, components of the extracellular matrix and growth factors, activate complement and release reactive oxygen species.
- Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis
A severe autoimmune disease that mainly affects small vessels in various organs (including the kidney in up to 80% of patients) and is characterized by the presence of ANCA antibodies in serum, excessive neutrophil activation and release of pro-inflammatory cytokines, reactive oxygen species and lytic enzymes.
- T cell-mediated rejection
(TCMR). Recognition of mismatched donor antigens (mainly represented by highly polymorphic major histocompatibility complex molecules), which results in priming of effector T cells against these alloantigens and ultimately leads to allograft rejection.
- Antibody-mediated rejection
(ABMR). Allograft rejection due to the recognition of mismatched donor major histocompatibility complex molecules by recipient B cells; effective treatments that can halt donor-specific antibody-mediated rejection are currently not available and this type of graft rejection is thus associated with poor prognosis.
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Kaminski, H., Couzi, L. & Eberl, M. Unconventional T cells and kidney disease. Nat Rev Nephrol 17, 795–813 (2021). https://doi.org/10.1038/s41581-021-00466-8