Aging unconventionally: γδ T cells, iNKT cells, and MAIT cells in aging

Abstract

Unconventional T cells include γδ T cells, invariant Natural Killer T cells (iNKT) cells and Mucosal Associated Invariant T (MAIT) cells, which are distinguished from conventional T cells by their recognition of non-peptide ligands presented by non-polymorphic antigen presenting molecules and rapid effector functions that are pre-programmed during their development. Here we review current knowledge of the effect of age on unconventional T cells, from early life to old age, in both mice and humans. We then discuss the role of unconventional T cells in age-associated diseases and infections, highlighting the similarities between members of the unconventional T cell family in the context of aging.

Keywords: Aging; Cancer; Gamma delta T cells; INKT cells; Inflammaging; MAIT cells.

Fig. 1

Conventional and unconventional T cells. T cells can be broadly grouped as conventional or unconventional based on their restriction molecules, while both groups of T cells can either be “innate-like” or “adaptive” depending on their innate-ness. Conventional T cells are MHC-restricted T cells that express TCRs composed of highly variable αβ chains, while unconventional T cells are non-MHC restricted T cells that recognise non-peptide, non-polymorphic antigen-presenting molecules and express either αβ or γδ TCRs. Within unconventional T cells, γδ T cells that express the Vδ2 chain are mostly Vγ9+Vδ2+ T cells which express the innate-like T cell transcription factor promyelocytic leukaemia zinc finger (PLZF) and are “innate-like” compared to γδ T cells that express the Vδ1 chain, which have been shown to have more adaptive biology. MAIT cells and iNKT cells also express PLZF, have a semi-invariant TCR and are considered “innate-like”. Within conventional T cells, memory CD4+ and CD8+ T cells are adaptive, while the recently discovered T_MIC (MHC II-restricted, innate-like, and commensal reactive T cells) are “innate-like”, expressing PLZF and with the ability to be activated in a TCR-independent manner, despite being MHC class II-restricted. Created with Biorender.com.

Fig. 2

Ligands and functions of unconventional human T cells. Overview of ligands recognised by human γδ T cells, MAIT cells, and iNKT cells compared with conventional CD4+ and CD8+ memory T cells, and effector molecules and functions associated with each subset. CD4+ T cells express a TCR comprised of variable αβ chain combinations, which recognise peptides by major histocompatibility complex (MHC) class II molecules, while CD8+ T cells also express variable αβ chain combinations which recognise peptides presented by MHC class I molecules. Binding of the canonical phosphoantigen HMBPP to BTN3A1/2A1 induces conformational change that allows BTN2A1 to bind to the semi-invariant γδ TCR composed of Vγ9 chain and Vδ2 chain. iNKT cells recognise glycolipid ligands presented by CD1d molecules through their semi-invariant TCR composed of Vα14-Jα18 and Vβ11 chains. MHC-related molecule 1 (MR1) presents riboflavin (vitamin B2) metabolites and intermediates to MAIT cells, which express a TCR comprising an invariant Vα7.2-Jα33 chain and preferential use of Vβ2 or 13 chains. Vδ2+ T cells, iNKT cells and MAIT cells can also be activated in a TCR-independent manner solely through cytokine receptors such as IL-12R, IL-18R, and IL-23R due to their expression of promyelocytic leukaemia zinc finger (PLZF), producing IFNγ and/or IL-17, and can be considered “innate-like” T cells. The main effector molecules produced by each of these T cell subsets are listed, and the main protective functions of these cells are highlighted in blue. HMB-PP= (E)− 4-hydroxy-3-methyl-but-2-enyl pyrophosphate, BTN=butyrophilin. *Amphiregulin from MAIT cells has been demonstrated to promote wound healing in mice and is upregulated at gene level in human MAIT cells upon TCR stimulation , but is yet to be demonstrated at the protein level in humans. Schematic based on . Created with Biorender.com.

Fig. 3

Aging of unconventional T cells in humans. A) Schematic of unconventional T cell frequencies within T cells over the human lifespan, based on current data. Within γδ T cells in cord blood, the Vδ1+ subset is the dominant γδ T cell subset but the Vδ2+ subset expands rapidly after birth, comprising most of the γδ T cell population by 1 years. MAIT cells also rapidly expand after birth, comprising most of the CD161++Vα7.2+ population by 1 years. MAIT cells and Vδ2+ populations increase to reach adult levels in early childhood, peaking around 25 years of age, and then decline with advancing age thereafter. iNKT cells remain relatively stable between birth and adulthood and may gradually decline over time depending on the cohort. Based on γδ T cell data from , and literature reviews from , , , MAIT cell data from , , , iNKT cell data from , , . Gender and geographic origin/race may have an effect on average frequencies, particularly in γδ T cells as the Vδ1+ population expands in CMV-seropositive donors , and MAIT cell frequencies are lower in non-western countries . Age-dependent decline of MAIT cells and Vδ2+ cells is faster in males. B) Schematic of conventional CD4+ and CD8+ T cell memory subset frequencies within T cells over the human lifespan, shown for comparison. Memory subsets are defined by CCR7 and CD45RA expression, where naïve T cells are CCR7+CD45RA+, central memory T cells (T_CM) are CCR7+CD45RA‐, effector memory T cells (T_EM) are CCR7-CD45RA-, and terminally differentiated T cells (T_EMRA) are CCR7‐CD45RA+. Naïve cells decrease with age while memory T cell subsets increase with age, with the CD8+ T cells in particular becoming dominated by memory subsets in the elderly. Conventional T cell data is based on , . Created with Biorender.com.

Fig. 4

Effect of aging on unconventional T cells in humans and mice. Schematic of the effect of aging in humans and mice on unconventional T cells, based on current data. The effects of aging on γδ T cells, iNKT cells and MAIT cells are summarised, with findings from human studies on the left and murine studies on the right. The consequences of these effects as demonstrated in mouse models referred to in the text are highlighted in red or green boxes, with red showing where they have been shown to play a pathogenic role and green showing a protective role. In general, there is consistent increase in IL-17-producing γδ T cells and iNKT cells in certain tissues in aged mice, and a reduction in Vγ9+Vδ2+ T cells and MAIT cells in human blood. *The reduction of iNKT cells in human blood with age is cohort dependent. The effect of aging in MAIT cells in mice and consequences of these effects in humans remains to be explored. LN=lymph node, pLN=peripheral lymph node, IEL=intraepithelial lymphocytes, WNV= West Nile Virus, HSV2 =herpes simplex virus 2, PMA/I = PMA/ionomycin, VAT=visceral adipose tissue, MODS=multi-organ dysfunction syndrome. Created with Biorender.com.