Marilen Benner

CHAPTER 3 64 Although it is well established that CD4 + T cells recognize major histocompatibility complex (MHC) class II molecules, MHC class I-restricted CD4 + T cells have been reported (42). Decidual PD1 HI Tregs somewhat resemble Tr1 cells that have been extensively characterized in murine tissues (43) and human peripheral blood (30, 44). Their similarities include the high expression of PD1, IL-10, IFN ɣ , and granzymes and the lack of FOXP3 expression. In contrast to Tr1 cells that were shown to depend on the ILT2-HLA-G pathway for their induction (45), induction of PD1 HI cells by EVTs was not dependent on the HLA-G receptor ILT2, while directly blocking HLA-G during the EVT and CD4 T cell co-culture resulted in a small but not significant decrease of PD1 HI Tregs induction. Tr1 cells were also shown to be induced by DC-10 through IL-10 secretion and interaction of HLA-G and ILT4 (46). Thus, other decidual cell types such as HLA-G + DC-10, that are found in decidual tis sues may contribute to induction of the PD1 HI Tregs described here (47). The main mechanisms of Tr1-mediated suppression are the secretion of IL-10 and killing of APCs by granzyme B (48). The expression of perforin and granzymes in first-trimester decidua PD1 HI Tregs may suggest they can also diminish APC activity using this pathway. Tr1 cells were identified in HLA-mismatched fetal liver hematopoietic stem cell transplant (HSCT) patients and were shown to suppress allogeneic responses in transplant patients and prevent autoimmune responses (31, 49). While the specificity of decidual PD1 HI Tregs remains unknown, the requirement for direct cell-cell contact with EVTs for their induction, as well as the role for the TCR co-receptor CD3, may provoke speculation that decidual PD1 HI IL-10 Tregs have specificity for fetal allo-antigens expressed by EVTs (e.g., HLA-C). In comparison with decidual PD1 HI Tregs, decidual CD25 HI FOXP3 + Tregs had an increased capacity to suppress proliferation and a more potent capacity to suppress IFN ɣ and TNF ɑ production by CD4 + and CD8 + Teffs. Thus, the mechanisms of suppression utilized by CD25 HI FOXP3 + Tregs and PD1 HI Tregs as well as the effects on their cellular targets are inherently different. The increased levels of co-inhibitory proteins and/or mRNAs (e.g., CTLA-4, GITR, CD39, ST2, LRRC32) expressed by decidual CD25 HI FOXP3 + Tregs compared to blood CD25 HI FOXP3 + Tregs suggests increased Treg activation and suppressive function in decidual tissue to regulate inflammation at the maternal- fetal interface. Furthermore, it demonstrates that decidual Tregs may utilize distinct molecular mechanisms of immune modulation against a variety of cellular targets beyond the inhibition of CD4 + and CD8 + Teff responses. The question of whether decidual Tregs are nTregs generated in the thymus with specificity for self-antigens or iTregs generated in the periphery with specificity for paternal antigens is immunologically interesting and of clinical relevance. It was previously reported that HELIOS is a marker of thymic-derived Tregs, while HELIOS - Tregs were induced from FOXP3 - T cells in the periphery (50). HELIOS and FOXP3 double-positive Tregs had increased suppressive capacity, more stable FOXP3 expression, and dissimilar TCR repertoire compared to HELIOS - FOXP3 + Tregs (51, 52). Instability of HELIOS-deficient Tregs was also associated with conversion to a T-effector phenotype and enhanced antitumor immunity (53), and HELIOS was shown to control