The Rapid Induction of HLA-E Is Essential for the Survival of Antigen-Activated Naive CD4 T Cells from Attack by NK Cells

Abstract

Increasing evidence shows that NK cells regulate adaptive immunity, but the underlying mechanisms are not well understood. In this study, we show that activated human NK cells suppress autologous naive CD4 T cell proliferation in response to allogeneic dendritic cells (DCs) by selectively killing Ag-activated T cells. Naive CD4 T cells, which were initially resistant to NK cell-mediated cytotoxicity, became substantially susceptible to NK cells within a day after priming with DCs. Ag-activated T cells showed various degrees of susceptibility to NK cells. After 1 d of priming with LPS-matured DCs, T cells were less susceptible to NK cells than were T cells primed with TNF-α–matured DCs. Subsequently at day 3, Ag-activated T cells regained resistance to NK cells. The level of HLA-E expression on Ag-activated T cells was closely correlated with resistance to NK cells. HLA-E was highly expressed at day 1 by T cells primed with LPS-matured DCs but not by T cells primed with TNF-α–matured DCs. An Ab blockade revealed a critical role for the HLA-E–NKG2A interaction in the protection of Ag-activated T cells from NK cells. Collectively, this study demonstrates that NK cells impact adaptive immunity through the finely controlled kinetics of HLA-E expression on T cells. Thus, HLA-E may be a new target for immunoregulation.

NK Cells and Their Ability to Modulate T Cells during Virus Infections

“…Upon activation, human CD4+ T cells rapidly upregulate HLA-E, a ligand for NKG2A. 184 This interaction was shown to be protective as blocking antibodies to either NKG2A or HLA-class I resulted in greatly increased NK cell killing. 177,184 The homolog to HLA-E in mice is Qa-1, which is primarily found presenting the Qdm peptide and interacts with NKG2A to deliver an inhibitory signal.…”

“…184 This interaction was shown to be protective as blocking antibodies to either NKG2A or HLA-class I resulted in greatly increased NK cell killing. 177,184 The homolog to HLA-E in mice is Qa-1, which is primarily found presenting the Qdm peptide and interacts with NKG2A to deliver an inhibitory signal. Using either Qa1-knockout mice or a Qa1 mutant that is unable to bind to NKG2A, a study showed that this interaction was critical for protecting T cells from NK cell lysis in vivo .…”

Activating KIR2DS5 receptor is a risk for thyroid cancer

“…Accumulation of NK cells in tumor sites may play a paradoxical role in the immune system response. Of particular interest are reports that NK cells eliminate the immature dendritic cells [40] and activated T cells [41], as well as down regulate T cell response [42]. We postulate that in the face of a neoplastic and inflammation condition, NK cells increase disease susceptibility if they carry a dominant activating KIR receptor repertoire (3DS1 pos , 2DS1 pos , and 2DS5 pos ).…”

Immunobiology of HLA Class-Ib Molecules in Transplantation

“…Clearly, then, high polyreactive HLA antibodies, raised against HLA-Ib molecules, play a role in graft acceptance by suppressing alloreactive T and B cells. In addition, it was shown that alloantigen-activated CD4 + T cells express HLA-E on their surface, resulting in an increased resistance to NK cells [90], thus suggesting a role in the regulation and differentiation of CD4 + T cells in vivo; those T cells also use HLA-E as a potential immunoregulatory therapeutic target for transplant patients. More studies are needed to evaluate the effect of polyreactive and monospecific HLA-Ib antibodies in transplantation, especially in terms of the presence of non-DSA in the sera of transplanted patients.…”

“…Therefore, it is still debatable whether HLA-Ib alleles should be matched for all transplants, and if so, whether the immunosuppressive function of HLA-Ib molecules is mediated by the donor's molecules or those of the recipient. Some studies emphasize that the allograft (donor cells) should be expressing HLA-Ib molecules-and at high levels-in order to evade the cytotoxic activity of NK cells and CD8+ T cells that lead to graft rejection [18,[87][88][89] because cell-to-cell contact is mandatory for the interaction of HLA-Ib molecules and their inhibitory receptors to prevent the lysis of allograft cells by NK cells and CD8+ T cells [90]. Promoting the expression of HLAIb-rather than sHLA-Ib-by the donor's cells therefore provides the best and most specific strategy for helping allograft cells evade cell-mediated damage (or rejection).…”