Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize bacterial ligands. Here, we demonstrate that MAIT cells are also activated during human viral infections in vivo. MAIT cells activation was observed during infection with dengue virus, hepatitis C virus and influenza virus. This activation—driving cytokine release and Granzyme B upregulation—is TCR-independent but dependent on IL-18 in synergy with IL-12, IL-15 and/or interferon-α/β. IL-18 levels and MAIT cell activation correlate with disease severity in acute dengue infection. Furthermore, HCV treatment with interferon-α leads to specific MAIT cell activation in vivo in parallel with an enhanced therapeutic response. Moreover, TCR-independent activation of MAIT cells leads to a reduction of HCV replication in vitro mediated by IFN-γ. Together these data demonstrate MAIT cells are activated following viral infections, and suggest a potential role in both host defence and immunopathology.

CD8 + T lymphocytes play a key role in host defense, in particular against important persistent viruses, although the critical functional properties of such cells in tissue are not fully defined. We have previously observed that CD8 + T cells specific for tissue-localized viruses such as hepatitis C virus express high levels of the C-type lectin CD161. To explore the significance of this, we examined CD8 + CD161 + T cells in healthy donors and those with hepatitis C virus and defined a population of CD8 + T cells with distinct homing and functional properties. These cells express high levels of CD161 and a pattern of molecules consistent with type 17 differentiation, including cytokines (e.g., IL-17, IL-22), transcription factors (e.g., retinoic acid-related orphan receptor γ-t, P = 6 × 10 −9 ; RUNX2, P = 0.004), cytokine receptors (e.g., IL-23R, P = 2 × 10 −7 ; IL-18 receptor, P = 4 × 10 −6 ), and chemokine receptors (e.g., CCR6, P = 3 × 10 −8 ; CXCR6, P = 3 × 10 −7 ; CCR2, P = 4 × 10 −7 ). CD161 + CD8 + T cells were markedly enriched in tissue samples and coexpressed IL-17 with high levels of IFN-γ and/or IL-22. The levels of polyfunctional cells in tissue was most marked in those with mild disease ( P = 0.0006). These data define a T cell lineage that is present already in cord blood and represents as many as one in six circulating CD8 + T cells in normal humans and a substantial fraction of tissue-infiltrating CD8 + T cells in chronic inflammation. Such cells play a role in the pathogenesis of chronic hepatitis and arthritis and potentially in other infectious and inflammatory diseases of man.

Human mucosal associated invariant T (MAIT)CD8 IntroductionHuman mucosal associated invariant T cells (MAIT) are defined by an invariant usage of the T-cell receptor chain V␣ 7.2, restriction by the major histocompatibility complex (MHC)-related protein MR1, and most recently have been shown to exhibit high expression of the C-type lectin CD161 (CD161 ϩϩ ), and IL18R. 1 Human MAIT cells have been described to be CD8␣␤, CD8␣␣, or doublenegative (DN) although a differential role for these different subsets has not been explored. Independently, we have described a human tissue-homing CD161 ϩϩ CD8 ϩ T-cell subset to be Tc17 cells, enriched at inflammatory sites including liver and joints. 2 Type-17 function has been recently confirmed in the MAIT cell population. 3 CD161 ϩϩ CD8 ϩ and MAIT-cells share key differentiation factors with Th17 cells, including cytokine expression (IL-17A and IL22), transcription factors (ROR␥t and RUNX2), chemokine receptors (CCR6 and CCR2), and cytokine receptors (IL23R and IL18R). There is growing recognition that these data describe the same phenomenon in parallel or overlapping populations, although this has not been fully defined to date, and the relationship between the 2 subsets remains unclear. Given the recent emergence of these cell types in diverse diseases, including multiple sclerosis, 4 this remains a significant unanswered question.CD161 was first identified as a potential lineage identifier for human Th17 cells when it was found to be a highly up-regulated gene on microarray comparison of gene expression between Th1, Th2, and Th17 clones, and circulating Th17 cells were contained within the CCR6 ϩ CD161 ϩ CD4 ϩ population. 5 Cord blood CD161 ϩ CD4 ϩ CD8 Ϫ , CD8 ϩ CD4 Ϫ and CD4 Ϫ CD8 Ϫ TCR␣␤ ϩ , and TCR␥␦ ϩ cells already express IL-23R and ROR␥t mRNA, and produce IL-17, unlike their CD161 counterparts. The transcription factor ROR␥t has been defined as the driver for the hallmark features of these cells, as CD161, IL-23R, and IL-17 expression could be directly induced by RORC2 transduction of CD161-cord cells. 6 In humans, CD161/NKR-P1A encoded by the KLRB1 gene, is expressed by a wide variety of human immune cells; natural killer (NK) cells, NK T cells, CD4 ϩ T cells, CD8 ϩ T cells, and ␥␦ T cells. Lectin-like transcript-1 (LLT1) 7,8 and PILAR 9 have been identified as ligands for CD161, although the role of such ligation on CD161 ϩϩ CD8 ϩ / MAIT-cells remains to be defined.NK T cells and MAIT-cells are the only lymphocyte populations to have a restricted TCR repertoire and restricting MHC molecule that is conserved between species. NK T cells are more abundant in mice, whereas MAIT-cells are more numerous in man, representing up to 15% of human CD8 ϩ T cells. Their developmental pathways are distinct. NK T cells are selected, expand and develop their innate-like phenotype, and function before exit from the thymus. They already express the transcription factor ZBTB16, which is crucial for their ready innate/effector functions. 10-12 MAIT-cells are naive and low in number i...

Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, >90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations.