Providence of the CD25⁺KIR⁺CD127⁻FOXP3⁻CD8⁺ T‐cell subset determines the dynamics of tumor immune surveillance

Abstract

CD8 T-regulatory (Treg) cells are emerging as crucial components of immune system. Previous studies have reported the presence of FOXP3 CD8 Treg cells, similar to CD4 Tregs, in cancer patients which produce high levels of the immunosuppressive cytokines, IL10 and TGFβ. At an early stage of tumor development, we have identified a subset of FOXP3 CD8 CD25 KIR CD127 Treg-like cells, which are IFNγ . However, this early-induced CD8 CD25 CD127 T-cell subset is certainly distinct from the IFNγ CD8 T-effector cells. These CD8 CD25 CD127 T cells express other FOXP3 CD8 Treg cell signature markers, and can selectively suppress autoreactive HLA-E T cells as well as tumor-induced CD4 Treg cells. In contrast to FOXP3 CD8 Tregs, this subset does not inhibit effector T-cell proliferation or their functions as they are HLA-E . Adoptive transfer of this early-CD8 Treg-like subset restrained tumor growth and inhibited CD4 Treg generation that impedes the immune surveillance and impairs cancer immunotherapy. At the late stage of tumor development, when CD4 Treg cells dominate the tumor-microenvironment, CD4 Tregs mediate the clonal deletion of these tumor-suppressive FOXP3 IFNγ CD8 CD25 CD127 T cells and ensure tumor immune evasion. Our findings suggest that at an early stage of the tumor, this tumor-induced IFNγ-producing FOXP3 CD8 CD25 CD127 T-cell subset can potentiate immune surveillance by targeting HLA-E-restricted CD4 Treg cells while leaving the effector T-cell population unaffected. Hence, manipulating their profile can open up a new avenue in cancer immunotherapy.

KIR + CD8 + T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19

“…Previous studies have shown that KIR + CD8 + T cells are terminally differentiated cells and display a restricted TCR repertoire ( 9 , 30 ), which is consistent with our findings. Correlations between KIR + CD8 + T cells and tumor immune surveillance ( 31 , 32 ) or chronic viral infections ( 33 , 34 ) have been reported, but the suppressive functions of this population have not been clearly defined previously. We demonstrate the regulatory function of KIR + CD8 + T cells toward pathogenic CD4 + T cells through an in vitro functional assay using PBMCs from CeD patients.…”

KIR+ CD8+ T Lymphocytes in Cancer Immunosurveillance and Patient Survival: Gene Expression Profiling

“…Different reports have evidenced that KIR+ CD8+ T lymphocytes were expanded in patients with tumors due to chronic antigenic stimulation [ 14 ]. However, more recent results described that, at early stages of tumor development, tumor-induced IFNγ-producing KIR+ CD25+ CD127− FOXP3− CD8+ T cells can potentiate immune surveillance by targeting human leukocyte antigen (HLA)-E-restricted CD4+ regulatory T cells (Treg) while leaving the effector T cell population unaffected [ 15 ]. At a later stage of tumor development, when CD4+ Treg cells dominate the tumor-microenvironment, CD4+ Tregs mediate the clonal deletion of these tumor-suppressive KIR+ IFNγ+ CD25+ CD8+ T cells and ensure tumor immune evasion.…”

“…At a later stage of tumor development, when CD4+ Treg cells dominate the tumor-microenvironment, CD4+ Tregs mediate the clonal deletion of these tumor-suppressive KIR+ IFNγ+ CD25+ CD8+ T cells and ensure tumor immune evasion. Besides, at later stages of tumor development a FOXP3+ TGFβ+ CD25+ CD127− CD8+ T cell population is expanded [ 15 ].…”

KIR and HLA-C genes in male infertility

“…Since the role of inflammatory response and infection is postulated in male infertility, and thus also the participation of natural killer (NK) cells and T lymphocytes, perhaps the role of killer immunoglobulin-like receptor (KIR) and its ligands may be presumed. KIR receptors play a central role in the control of NK cell function, but may also be expressed by some lymphocytes [ 7 – 10 ]. KIR can be of inhibitory or activating function.…”