NKG2A is a marker for acquisition of regulatory function by human CD8⁺ T cells activated with anti‐CD3 antibody

Abstract

Summary Treatment with anti-CD3 mAbs modulates immune responses that cause Type 1 diabetes and other diseases. CD8+ Tregs can be induced in vitro and in vivo by the mAb. However, 1/3 of patients do not respond to drug therapy and in an equal proportion, anti-CD3 mAb does not induce Tregs in vitro. The acquisition of CD8+ Treg activity is a function of the CD8+ cells and not the targets in the assay. To identify markers to differentiate responses of CD8+ Tregs, we analyzed genes differentially expressed in CD8+ T cells of non-responders compared to responders, and found that an inhibitory receptor NKG2A (CD159a) was highly expressed in cells from all non-responders tested. An agonistic mAb to NKG2a during in vitro CD8+ Treg induction by anti-CD3 prevented induction of CD8+ Tregs. CD8+ T cells that are TNFR2+ but NKG2A− are the most potent induced Tregs. The level of NKG2A expression on resting CD8+ T cells inversely correlated with acquisition of regulatory function when activated. We suggest that induction of human CD8+ Tregs by anti-CD3 mAb is controlled by a negative signaling through NKG2A, and that NKG2A may serve as a negative marker of human CD8+ Tregs.

Humanized Mice as a Model for Aberrant Responses in Human T Cell Immunotherapy

“…In addition, it is possible that increases in the pro-inflammatory cytokine TNF, interferes with Treg suppressive function as has been described in rheumatoid arthritis (50) and antibiotic refractory Lyme arthritis (51). Finally, teplizumab treatment appeared to increase Treg number and restore function in a manner not unlike we and others previously demonstrated in treated human patients(52-54). We found that there were increased numbers of Tregs and enhanced function reflected by the increase in constitutively phosphorylated STAT5.…”

Changes in T‐cell subsets identify responders to FcR‐nonbinding anti‐CD3 mAb (teplizumab) in patients with type 1 diabetes

“…A number of mechanisms of anti-CD3 mAbs have been suggested. Previous studies from our group and others showed induction of subpopulations of regulatory T cells [15][16][17][18]. Recent work has suggested that adaptive regulatory T cells that produce IL-10 and/or TGF-β may be induced following migration of T cells to the gut following treatment with teplizumab [19,20].…”

“…Interestingly, we also found lower levels of expression of KLRC1 (NKG2A). In previous studies, we had shown that low expression of NKG2A identified CD8 + T cells with regulatory function from teplizumab‐treated subjects .…”

Tuberculosis patients display a high proportion of CD8+ T cells with a high cytotoxic potential

“…NKG2D is an activating receptor expressed on the surface of NK cells and CD8 + T cells. The NKG2A inhibitor receptor is expressed on T cells only under specific conditions and after a long culture time . In PBMCs from TB patients and healthy controls, we identified the frequency of CD8 + cells that coexpress NKG2D and NKG2A (Figure a,c, respectively).…”