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KIRs mark killers suppressing autoimmunity

2022; Cell Press; Volume: 55; Issue: 5 Linguagem: Inglês

10.1016/j.immuni.2022.04.014

1097-4180

June‐Young Koh, Eui–Cheol Shin,

Reproductive System and Pregnancy

Identification of regulatory CD8+ T cells that suppress pathological immune responses is an importunate pursuit. In a recent issue of Science, Li et al. demonstrated that human KIR+CD8+ T cells suppress autoimmunity by eliminating pathogenic CD4+ T cells. Identification of regulatory CD8+ T cells that suppress pathological immune responses is an importunate pursuit. In a recent issue of Science, Li et al. demonstrated that human KIR+CD8+ T cells suppress autoimmunity by eliminating pathogenic CD4+ T cells. CD8+ T cells and natural killer (NK) cells are lymphocytes that exert cytotoxic functions, but they have distinct characteristics as adaptive and innate immune cells, respectively. CD8+ T cells are activated by T cell receptor (TCR), whereas NK cell activity is regulated by a balance between inhibitory and activating signals. Human NK cells express killer-cell immunoglobulin-like receptors (KIRs) that recognize major histocompatibility complex class I (MHC-I) molecules and deliver inhibitory signals via cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) (Lanier, 2005Lanier L.L. NK cell recognition.Annu. Rev. Immunol. 2005; 23: 225-274https://doi.org/10.1146/annurev.immunol.23.021704.115526Crossref PubMed Scopus (2313) Google Scholar). In humans, KIRs are also expressed by a minor subset of CD8+TCRαβ+ T cells. KIR+CD8+ T cells are present in the spleen and lymph nodes, as well as in the peripheral blood at a frequency of ∼4.5% among total T cells in healthy adults (Bjorkstrom et al., 2012Bjorkstrom N.K. Beziat V. Cichocki F. Liu L.L. Levine J. Larsson S. Koup R.A. Anderson S.K. Ljunggren H.G. Malmberg K.J. CD8 T cells express randomly selected KIRs with distinct specificities compared with NK cells.Blood. 2012; 120: 3455-3465https://doi.org/10.1182/blood-2012-03-416867Crossref PubMed Scopus (82) Google Scholar). In human CD8+ T cells, continuous TCR stimulation or repetitive homeostatic cytokine treatment can upregulate the expression of KIRs, and KIR+CD8+ T cells accumulate with age (Huard and Karlsson, 2000Huard B. Karlsson L. KIR expression on self-reactive CD8+ T cells is controlled by T-cell receptor engagement.Nature. 2000; 403: 325-328https://doi.org/10.1038/35002105Crossref PubMed Scopus (121) Google Scholar). KIR+CD8+ T cells tend to exhibit a phenotype of CD27−CD28−CD45RA+CD57+, which is compatible with a terminally differentiated phenotype with restricted TCR repertoire (Vivier and Anfossi, 2004Vivier E. Anfossi N. Inhibitory NK-cell receptors on T cells: witness of the past, actors of the future.Nat. Rev. Immunol. 2004; 4: 190-198https://doi.org/10.1038/nri1306Crossref PubMed Scopus (189) Google Scholar). However, KIR expression is barely detectable among CD8+ T cells specific to cytomegalovirus or HIV. Although such phenotypic information about KIR+CD8+ T cells is known, their functional role has not yet been demonstrated in humans. In mice, NK cells express Ly49 receptors. Human KIRs and mouse Ly49 share several common features, including MHC-I binding and the delivery of inhibitory signals through ITIMs (Lanier, 2005Lanier L.L. NK cell recognition.Annu. Rev. Immunol. 2005; 23: 225-274https://doi.org/10.1146/annurev.immunol.23.021704.115526Crossref PubMed Scopus (2313) Google Scholar). Ly49 is also expressed by a minor subset of CD8+ T cells in mice, similar to KIRs in humans. Intriguingly, Ly49+CD8+ T cells that also express high levels of CD122 have been identified as regulatory CD8+ T cells in a series of studies (Kim and Cantor, 2011Kim H.J. Cantor H. Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells.Semin. Immunol. 2011; 23: 446-452https://doi.org/10.1016/j.smim.2011.06.001Crossref PubMed Scopus (77) Google Scholar). Given that Ly49+CD8+ T cells are regulatory T cells in mice, Li et al. paid attention to KIR+CD8+ T cells in patients with autoimmune diseases in their recent study (Li et al., 2022Li J. Zaslavsky M. Su Y. Guo J. Sikora M.J. van Unen V. Christophersen A. Chiou S.H. Chen L. Li J. et al.KIR(+)CD8(+) T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.Science. 2022; 376: eabi9591https://doi.org/10.1126/science.abi9591Crossref PubMed Scopus (65) Google Scholar). First, they found that patients with multiple sclerosis, systemic lupus erythematosus (SLE), or celiac disease have significantly increased frequencies of KIR+CD8+ T cells compared to healthy donors in not only peripheral blood, but also pathological tissues. In addition, the frequency of KIR+CD8+ T cells significantly increases in patients with coronavirus disease 2019 (COVID-19) or influenza, particularly in COVID-19 patients with severe disease or vasculitis. However, the frequency of FoxP3+CD4+ regulatory T cells does not increase in patients with autoimmune diseases or COVID-19. The authors investigated functions of KIR+CD8+ T cells and showed that KIR+CD8+ T cells suppress antigen-stimulated proliferation of pathogenic CD4+ T cells. In this assay using peripheral blood mononuclear cells from patients with celiac disease, in vitro stimulation by deamidated gluten led to robust proliferation of gliadin-specific CD4+ T cells in the absence of KIR+CD8+ T cells, but the proliferation was significantly decreased by the addition of KIR+CD8+ T cells. This suppressive activity partially depends on classical MHC-I and HLA-E (non-classical MHC-I). They further found that KIR+CD8+ T cells eliminate gliadin-specific CD4+ T cells by inducing apoptosis in a contact-dependent manner (Figure 1). These findings are reminiscent of mouse Ly49+CD8+ regulatory T cells in terms of dependence on perforin and both classical and non-classical MHC-I molecules (Kim and Cantor, 2011Kim H.J. Cantor H. Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells.Semin. Immunol. 2011; 23: 446-452https://doi.org/10.1016/j.smim.2011.06.001Crossref PubMed Scopus (77) Google Scholar). Transcriptional analysis also verified that KIR+CD8+ T cells are the human equivalent of mouse Ly49+CD8+ regulatory T cells. KIR+CD8+ T cells exhibit upregulation of genes for cytotoxic and NK-cell-associated molecules and Helios, a regulatory T-cell-associated transcription factor, which was confirmed at the protein level. Such transcriptional features are commonly observed in KIR+CD8+ T cells from healthy donors and patients with autoimmune diseases or COVID-19. Single-cell analysis of transcriptomes and TCR sequences revealed heterogeneous sub-populations among KIR+CD8+ T cells, including clonally expanded and unexpanded sub-populations. Expanded KIR+CD8+ T cells exhibit upregulation of genes associated with cytotoxicity, effector T cells, and type I interferon (IFN) responses and downregulation of genes related to naive and memory T cells, indicating that KIR+CD8+ T cells differentiate into effector T cells and suppress pathogenic CD4+ T cells via a cytotoxic mechanism after clonal expansion. TCR analysis showed restricted TCR usage among KIR+CD8+ T cells compared to KIR−CD8+ T cells, which is possibly grouped with the same antigen specificity. Ultimately, the authors investigated the role of regulatory CD8+ T cells using mice with Cre-mediated expression of diphtheria toxin A in Ly49F+ cells in which Ly49+CD8+ T cells are partially ablated (50–75% decrease). Ly49+CD8+ T-cell-ablated mice do not exhibit an abnormal immunological phenotype unless they are infected with a virus. Infection with lymphocytic choriomeningitis virus (LCMV) or influenza virus increases the frequency of Ly49+CD8+ T cells in wild-type mice; however, this response is blunted in Ly49+CD8+ T-cell-ablated mice. Importantly, Ly49+CD8+ T-cell-ablated mice exhibit an autoimmune pathology in the kidney after LCMV infection and severe inflammation in the lungs after influenza infection, but viral clearance and virus-specific CD4+ and CD8+ T cell responses are not affected, indicating that regulatory CD8+ T cells prevent the development of autoimmunity caused by viral infections. The concept of regulatory CD8+ T cells was initiated by a study of Qa-1-dependent T cell-T cell suppressive interactions in a mouse model of experimental autoimmune encephalomyelitis (Cantor et al., 1978Cantor H. Hugenberger J. McVay-Boudreau L. Eardley D.D. Kemp J. Shen F.W. Gershon R.K. Immunoregulatory circuits among T-cell sets. Identification of a subpopulation of T-helper cells that induces feedback inhibition.J. Exp. Med. 1978; 148: 871-877https://doi.org/10.1084/jem.148.4.871Crossref PubMed Scopus (115) Google Scholar). Subsequent studies revealed that Qa-1-dependent regulatory CD8+ T cells are marked by a CD122hiLy49+ phenotype (Kim et al., 2010Kim H.J. Verbinnen B. Tang X. Lu L. Cantor H. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance.Nature. 2010; 467: 328-332https://doi.org/10.1038/nature09370Crossref PubMed Scopus (283) Google Scholar). Qa-1-dependent immunosuppressive function of CD122hiLy49+CD8+ T cells was shown in a mouse model in which the Qa-1 interaction is abolished (Kim et al., 2010Kim H.J. Verbinnen B. Tang X. Lu L. Cantor H. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance.Nature. 2010; 467: 328-332https://doi.org/10.1038/nature09370Crossref PubMed Scopus (283) Google Scholar). In this mouse model, pathologic follicular helper T (TFH) cells were expanded and SLE features developed, demonstrating that CD122hiLy49+CD8+ T cells regulate hyper-activated Qa-1-expressing TFH cells. In addition, IL-15 was shown to support the development and function of CD122hiLy49+CD8+ T cells (Kim et al., 2011Kim H.J. Wang X. Radfar S. Sproule T.J. Roopenian D.C. Cantor H. CD8+ T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice.Proc. Natl. Acad. Sci. U S A. 2011; 108: 2010-2015https://doi.org/10.1073/pnas.1018974108Crossref PubMed Scopus (123) Google Scholar). Molecular mechanisms underlying the modulation of CD122hiLy49+CD8+ T cells were also revealed. TGF-β signal-induced Helios is required for stable suppressive functions of CD122hiLy49+CD8+ T cells, and Eomes contributes to the follicular homing capacity of CD122hiLy49+CD8+ T cells (Kim and Cantor, 2011Kim H.J. Cantor H. Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells.Semin. Immunol. 2011; 23: 446-452https://doi.org/10.1016/j.smim.2011.06.001Crossref PubMed Scopus (77) Google Scholar; Mishra et al., 2021Mishra S. Liao W. Liu Y. Yang M. Ma C. Wu H. Zhao M. Zhang X. Qiu Y. Lu Q. Zhang N. TGF-beta and Eomes control the homeostasis of CD8+ regulatory T cells.J. Exp. Med. 2021; 218: e20200030https://doi.org/10.1084/jem.20200030Crossref PubMed Google Scholar). On the basis of this background, Li et al. demonstrated that Ly49+CD8+ regulatory T cells suppress the development of viral-infection-induced autoimmunity. More importantly, they found that KIR+CD8+ T cells are the human equivalent of mouse Ly49+CD8+ regulatory T cells (Li et al., 2022Li J. Zaslavsky M. Su Y. Guo J. Sikora M.J. van Unen V. Christophersen A. Chiou S.H. Chen L. Li J. et al.KIR(+)CD8(+) T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.Science. 2022; 376: eabi9591https://doi.org/10.1126/science.abi9591Crossref PubMed Scopus (65) Google Scholar). Regarding KIR+CD8+ regulatory T cells, several questions remain to be answered. The most critical one is how KIR+CD8+ T cells recognize the target cells of suppression. Li et al. proposed that KIR+CD8+ T cells may recognize common antigens presented by classical and non-classical MHC-I molecules (Li et al., 2022Li J. Zaslavsky M. Su Y. Guo J. Sikora M.J. van Unen V. Christophersen A. Chiou S.H. Chen L. Li J. et al.KIR(+)CD8(+) T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.Science. 2022; 376: eabi9591https://doi.org/10.1126/science.abi9591Crossref PubMed Scopus (65) Google Scholar). They also provided indirect evidence that antigens for KIR+CD8+ T cells may exist under physiological and diverse pathological conditions by analyzing their TCR sequences using GLIPH2, an algorithm for TCR clustering with the same antigen specificity. In this regard, one of the interesting findings was that KIR+CD8+ T cells did not suppress influenza-virus-specific CD4+ T cells (Li et al., 2022Li J. Zaslavsky M. Su Y. Guo J. Sikora M.J. van Unen V. Christophersen A. Chiou S.H. Chen L. Li J. et al.KIR(+)CD8(+) T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.Science. 2022; 376: eabi9591https://doi.org/10.1126/science.abi9591Crossref PubMed Scopus (65) Google Scholar), indicating that only pathogenic CD4+ T cells are suppressed by KIR+CD8+ T cells. In addition, pre-activation of KIR+CD8+ T cells in the presence of anti-CD3/CD28 was required for their full suppressive activity (Li et al., 2022Li J. Zaslavsky M. Su Y. Guo J. Sikora M.J. van Unen V. Christophersen A. Chiou S.H. Chen L. Li J. et al.KIR(+)CD8(+) T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.Science. 2022; 376: eabi9591https://doi.org/10.1126/science.abi9591Crossref PubMed Scopus (65) Google Scholar). To recognize pathogenic CD4+ T cells, engagement of other receptors, possibly NK-cell-activating receptors, may be required in addition to TCR activation. Regulation of the suppressive functions of KIR+CD8+ T cells also needs to be investigated further. In this regard, the authors provided data suggesting that KIRs may negatively regulate the suppressive activity of KIR+CD8+ T cells (Li et al., 2022Li J. Zaslavsky M. Su Y. Guo J. Sikora M.J. van Unen V. Christophersen A. Chiou S.H. Chen L. Li J. et al.KIR(+)CD8(+) T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.Science. 2022; 376: eabi9591https://doi.org/10.1126/science.abi9591Crossref PubMed Scopus (65) Google Scholar); thus, KIRs are not just a marker of CD8+ regulatory T cells, but also a tight controller of them. In their study, Li et al. emphasized suppression of virus-infection-induced autoimmunity as a role of KIR+CD8+ T cells. They hypothesized that peripheral self-specific T cells surviving thymic selection are required to equip a complete T cell repertoire that covers diverse microbial pathogens (Li et al., 2022Li J. Zaslavsky M. Su Y. Guo J. Sikora M.J. van Unen V. Christophersen A. Chiou S.H. Chen L. Li J. et al.KIR(+)CD8(+) T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.Science. 2022; 376: eabi9591https://doi.org/10.1126/science.abi9591Crossref PubMed Scopus (65) Google Scholar). In this hypothesis, self-specific T cells can be activated during microbial infection and, consequently, autoimmunity can develop after infectious diseases. As shown by Li et al., a major role of KIR+CD8+ regulatory T cells may be the suppression of infection-induced autoimmunity by eliminating pathogenic CD4+ T cells with potential self-reactivity. In this regard, it is a question of whether other types of immune cells can also be eliminated by KIR+CD8+ T cells, including pathogenic self-reactive CD8+ T cells, autoantibody-producing B cells, and aberrantly hyper-activated cells. Although regulatory CD8+ T cells that suppress pathological immune responses have been studied for a long time, their nature has been elusive, particularly in humans. The recent study by Li et al. identifying KIR+CD8+ T cells as regulatory T cells will pave the way for understanding the pathogenesis of autoimmune diseases and the development of novel therapeutics for the treatment of autoimmune diseases. This work was supported by the Institute for Basic Science (IBS), Republic of Korea, under project code IBS-R801-D2. The authors declare no competing interests.