In:
Science, American Association for the Advancement of Science (AAAS), Vol. 376, No. 6590 ( 2022-04-15)
Abstract:
Previous studies have identified Ly49 + CD8 + T cells as a CD8 + T cell subset with regulatory functions in mice. These cells can suppress myelin oligodendrocyte glycoprotein (MOG)–specific pathogenic CD4 + T cells through their cytolytic activity and thereby ameliorate experimental autoimmune encephalomyelitis (EAE). However, whether a similar CD8 + regulatory T cell subset exists in humans and whether its suppressive activity extends beyond autoimmune diseases to play a more general role in peripheral tolerance remains to be determined. RATIONALE Because killer cell immunoglobulin-like receptors (KIRs) are the evolutionary counterpart of the mouse Ly49 family in humans, we investigated whether KIR + CD8 + T cells are the phenotypic and functional equivalent of mouse Ly49 + CD8 + T cells. We assessed the frequency of KIR + CD8 + T cells in human autoimmune and infectious diseases and analyzed their transcriptional profiles as well as T cell receptor (TCR) repertoires. Moreover, we developed an in vitro functional assay to test their regulatory functions on gliadin-specific disease-driving CD4 + T cells from patients with celiac disease (CeD) and to study the mechanisms of suppression. To further elucidate their role in infectious diseases, we analyzed the effects of selective ablation of their murine counterpart on the antiviral responses during infection and tissue pathology after resolution of viral infection. RESULTS The frequency of KIR + CD8 + T cells was higher in the blood and inflamed tissues of patients with multiple autoimmune diseases compared with those of healthy controls. Furthermore, the increase of duodenal KIR + CD8 + T cells positively correlated with disease activity in CeD. In vitro, KIR + CD8 + T cells were able to specifically eliminate gliadin-specific pathogenic CD4 + T cells from the leukocytes of CeD patients through their cytotoxicity in a class I major histocompatibility complex (MHC)–dependent manner. Moreover, our RNA sequencing (RNA-seq) analysis revealed many similarities between human KIR + CD8 + T cells and mouse Ly49 + CD8 + T cells, which suggests that KIR + CD8 + T cells are the functional and phenotypic equivalents of mouse Ly49 + CD8 + T cells in humans. The expression of inhibitory KIR receptors appeared to suppress the activation and cytotoxic functions of KIR + CD8 + T cells. Moreover, elevated levels of KIR + CD8 + T cells, but not CD4 + regulatory T cells (T regs ), were also observed in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)– or influenza-infected patients and correlated with vasculitis in COVID-19 patients. Notably, expanded KIR + CD8 + T cells from healthy subjects and different diseases displayed shared phenotypes and similar TCR sequences as revealed by single-cell RNA-seq and TCR sequencing (TCR-seq). Finally, the selective depletion of Ly49 + CD8 + T cells in virus-infected mice did not interfere with the antiviral responses but resulted in exacerbated autoimmunity after infection, demonstrating the critical role that this subset of CD8 + T regs plays in controlling harmful self-reactivity in infectious diseases. CONCLUSION We identify KIR + CD8 + T cells as an important regulatory T cell subset in humans. They are induced as part of the response during an autoimmune reaction or infection and may act as a negative feedback mechanism to specifically suppress the self-reactive or otherwise pathogenic cells without affecting the immune responses against pathogens. This subset of CD8 + T regs appears to play an important role in maintaining peripheral tolerance, which is distinct from and likely complementary to that of CD4 + T regs . Our findings also provide insights into understanding the relationship between autoimmunity and infectious diseases and into the development of potential therapeutic approaches targeting KIR + CD8 + T cells to suppress undesirable self-reactivity in autoimmune disorders and infectious diseases. The proposed role of CD8 + regulatory T cells in peripheral tolerance. KIR + CD8 + T cells are the equivalent of mouse Ly49 + CD8 + T cells in humans, with similar regulatory functions. During an infection, this kind of CD8 + regulatory T cell is induced and suppresses those CD4 + T cells with a strong reactivity to self, which may cause autoimmunity without interfering with the immune responses against pathogens.
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.abi9591
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2022
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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