Immune regulation by pretenders: cell-to-cell transfers of HLA-G make effector T cells act as regulatory cells

Abstract

Trogocytosis is the uptake of membrane fragments from one cell by another and has been described for immune cells in mice and humans. Functional consequences of trogocytosis are emerging, but a dramatic immune function has still to be associated with it. Here we show that some resting, and most activated, CD4 ؉ and CD8 ؉ T cells acquire immunosuppressive HLA-G1 from antigen-presenting cells (APCs) in a few minutes. Acquisition of HLA-G through membrane transfers does not change the real nature of the T cells but immediately reverses their function from effectors to regulatory cells. These regulatory cells can inhibit allo-proliferative responses through HLA-G1 that they acquired. These data demonstrate that trogocytosis of HLA-G1 leads to instant generation of a new type of regulatory cells, which act through cell-surface molecules they temporarily display but do not express themselves. Such regulatory cells whose existence is most likely limited in space and time might constitute an "emergency" immune suppression mechanism used by HLA-G-expressing tissues to protect themselves against immune aggression. In addition, T cells acquire from HLA-Gexpressing APCs their HLA-G-dependent capability to induce the slower differentiation of regulatory cells that act independently of HLA-G. These data re-emphasize the significance of HLA-G expression in normal and pathologic situations. Introduction"Trogocytosis" is a new name for "fast, cell-to-cell contactdependent uptake of membranes and associated molecules." 1 Trogocytosis has been documented in T and B lymphocytes, natural killer (NK) cells, antigen-presenting cells (APCs), and tumor cells (reviewed in Hudrisier and Bongrand 2 ). Most of the work on trogocytosis by T cells was done in the murine system, in which it was shown that CD4 ϩ and CD8 ϩ T cells acquired APC major histocompatibility complex (MHC) class II and MHC class I molecules, respectively, in an antigen-specific manner [3][4][5][6][7] : for trogocytosis to occur, T-cell receptor (TCR) engagement was necessary, and activation or anti-CD3 increased trogocytosis efficiency. 8,9 Yet, there is no strict dependence of trogocytosis on TCR engagement: (1) in some systems, trogocytosis was shown to depend on CD28 engagement 5 ; and (2) transfer of MHC class II antigens from APCs to T cells can occur in an all-autologous system. 8 Even though most of the work on APC material acquisition by T cells was done on MHC molecules, it was shown that costimulatory molecules B7-1 (CD80), B7-2 (CD86), and ICAM-1 (CD54) are also acquired by murine antigen-specific T cells. 5,10 Trogocytosis is a transfer of membrane fragments, not of individual molecules. Consequently, all molecules contained within a certain membrane area are transferred from one cell to another during trogocytosis, including some that might have nothing to do with the acquirer cell, or participate in cell-to-cell cross-talk. Thus, during trogocytosis, some molecules transfer passively. This was clearly evidenced by showing that CD8 ϩ T cells can acquire MH...

Human leukocyte antigen G polymorphism is associated with an increased risk of invasive cancer of the uterine cervix

“…17 In addition, HLA-G molecules can be transferred by trogocytosis to competent cytotoxic cells rendering them unresponsive to tumor antigens. 18 Several studies have demonstrated that cervical cancer tissue expressed HLA-G and that its expression correlates with tumor progression. [5][6][7][8]10 In this report, the wildtype HLA-G*01:01:01 allele conferred protection against invasive cancer, whereas variant HLA-G*01:01:02, -G*01:06 and -G*3 0 UTR 14-bp insertion alleles increased cervical cancer risk.…”

Intercellular Trogocytosis Plays an Important Role in Modulation of Immune Responses

“…HLA-G has been shown to transfer from APCs to T cells resulting in functional consequences. LeMoult et al (104) suggested that the HLA-G-associated trogocytosis could have a major impact on immune responses, with which highly efficient regulatory T cells could be generated by reversing the function of effector immune cells. They have emphasized the need for monitoring HLA-G expression in pathologic context and incorporation of HLA-G blocking strategies into immunotherapies.…”

NK resistance of tumor cells from multiple myeloma and chronic lymphocytic leukemia patients: implication of HLA-G

“…24 Recently, a new pathway of immune suppression by HLA-G has been described, which is mediated by immunosuppressive T and NK cells generated by acquisition of HLA-G through a process of membrane transfer called 'trogocytosis'. 25,26 The impact of this immune suppression can, therefore, be beneficial or detrimental depending on its scope, since by its immunoregulatory role, it may facilitate the acceptance of the fetus, allografts and tumors.…”