Aspects of helminth-associated T cell suppression: F4/80+ macrophage induction of anergy through IL-6 and PD-L1

When attached to an innate carrier molecule and injected into the peritoneal cavity, purified lacto-N-fucopentaose III (LNFPIII), an oligosaccharide present in the soluble fraction of Schistosoma mansoni egg antigen (SEA), drives the development or recruitment of F4/80 +/Gr-1+ myeloid cells able to suppress proliferation of newly stimulated T cells. Efforts to conclusively identify, define and describe the mechanism of myeloid cell-mediated T cell suppression have been frustrated by an over-reliance on imprecise definitions of suppressor cell phenotype and function. In this work, we refine the present suppressor cell phenotype, identify soluble and surface expressed mechanisms of suppression, and determine that suppression involves the induction of T cell anergy. In Chapter 2, we describe the kinetics of suppressor cell development and function over the course of S. mansoni infection. In Chapter 3, we characterized the suppressor cell population by determining that suppression required contact with target T cells and isolated an F4/80+(bright) /Gr-1+(dim) set of IL-6-expressing cells that appeared to be the source of suppressive activity in S. mansoni infection. Chapter 4 focused on the mechanism and functional significance of suppression. By examining how LNFPIII-Dextran and IL-6 impacted the expression of apoptotic and costimulatory surface markers, we identified two potential suppression markers, and associate suppressive activity to one of them, Programmed Death Ligand-I1 (PD-L1). Since PD-L1, a putative inducer of T cell anergy, appeared to be involved in suppression, we restimulated suppressed T cells and discovered that suppression leads to T cell anergy.