Mechanisms of antigen presentation to T cells in murine graft-versus-host disease: cross-presentation and the appearance of cross-presentation

Abstract

Recipient antigen-presenting cells (APCs) initiate GVHD by directly presenting host minor histocompatibility antigens (miHAs) to donor CD8 cells. However, later after transplantation, host APCs are replaced by donor APCs, and if pathogenic CD8 cells continue to require APC stimulation, then donor APCs must cross-present host miHAs. Consistent with this, CD8-mediated GVHD is reduced when donor APCs are MHC class I ؊ . To study cross-presentation, we used hosts that express defined MHC class I K b -restricted miHAs, crossed to K b -deficient backgrounds, such that these antigens cannot be directly presented. Cross-priming was surprisingly efficient, whether antigen was restricted to the hematopoietic or nonhematopoietic compartments. Cross-primed CD8 cells were cytolytic and produced IFN-␥. CD8 cells were exclusively primed by donor CD11c ؉ cells, and optimal cross-priming required that they are stimulated by both type I IFNs and CD40L. In studying which donor APCs acquire host miHAs, we made the surprising discovery that there was a large-scale trans- IntroductionAllogeneic hematopoietic stem cell transplantation (alloSCT) can be a life-saving therapy for hematologic malignancies and acquired or inherited nonmalignant disorders of blood cells. Mature donor T cells in allografts play important roles in alloSCT. They contribute to T-cell reconstitution in the recipient, promote donor hematopoietic engraftment, and mediate an anti-tumor effect called GVL. Unfortunately, donor T cells can broadly target host tissues causing GVHD. 1 Because of GVHD, all patients receive some type of prophylactic immunosuppression, either by depleting T cells from the allograft, or more commonly, with pharmacologic agents and that inhibit T-cell function. However, even with pharmacologic immunosuppression, GVHD remains a major cause of morbidity and mortality. Novel approaches are clearly needed.GVHD is initiated by antigen-presenting cells (APCs) that prime alloreactive donor T cells. 1 In MHC-matched alloSCT, donor T cells target minor histocompatibility antigens (miHAs), which are the peptide products of polymorphic genes that distinguish the host from the donor. We previously found that direct presentation of MHC class I-restricted miHAs by recipient APCs is necessary for CD8-mediated GVHD in an MHC-matched, multiple miHAmismatched model. 2 However, although host APCs are key players, there was reason to believe that donor APCs should also play a significant role, as GVHD can begin and persist at times after transplantation when host hematopoietic cells, including APCs, are largely if not completely replaced by donor-derived cells. If, at these later times, alloreactive CD8 cells still need to be primed by professional APCs to be pathogenic, one would predict that donor APCs crosspresenting host miHAs would be important. On the other hand, it is possible that GVHD is maintained by a small number of persistent host APCs. 3 In studies to address the role of donor APCs, we previously reported that CD8-mediated GVHD against miHAs is r...

Cross-Dressing by Donor Dendritic Cells after Allogeneic Bone Marrow Transplantation Contributes to Formation of the Immunological Synapse and Maximizes Responses to Indirectly Presented Antigen

“…This observation highlights the potential in vivo importance of crossdressing as a mechanism for supporting DC/T cell contact. Our results in these MHC class II-dependent assays contrast somewhat with studies in CD8 T cell-based systems wherein cross-dressed Ag appeared sufficient for the induction of proliferative responses (24). Purified cross-dressed DCs bearing MHC class I:SIINFEKL complexes acquired from recipient mice in vivo after BMT could induce low levels of proliferation in naive CD8 + OT-I T cells in vitro, although responses were surprisingly minimal in the positive controls in these studies (which were DCs from nontransplanted B6 animals in which OVA was secreted under control of the b-actin promoter) (24).…”

“…In addition to these two classical pathways, we have been interested in the semidirect pathway of Ag presentation, whereby a donor APC which has acquired MHC of host-type, via "trogocytosis" or "cross-dressing" could potentially stimulate antihost responses from donor T cells (7)(8)(9). This phenomenon has been studied with respect to CD8 T cell responses, and data suggest that both naive and memory CD8 T cells can respond to trogocytosed Ag using either proliferation or cytokine production as the measure of functional response (10)(11)(12)(13).…”

Acquisition of MHC:Peptide Complexes by Dendritic Cells Contributes to the Generation of Antiviral CD8+ T Cell Immunity In Vivo

“…Alternatively, MHC class I:peptide complexes may be transferred through acquisition of plasma membrane from living or dying cells (40,41). Regardless of the mechanism involved, what is evident from our earlier in vitro data, and that of others, and also the data presented in this work, is that transferred MHC class I:peptide complexes are capable of activating Ag-specific CD8 + T cells (10,11,15,42).…”

“…Recently, a third mechanism known as cross-dressing has been proposed to contribute to antiviral immunity, whereby an uninfected APC acquires pre-existing MHC class I:peptide molecules from a virus-infected cell (9)(10)(11). In support of such a role, we, and others, have shown that MHC class I:peptide complexes can be acquired by immature and mature dendritic cells (DCs) both in vitro and in vivo (10)(11)(12)(13)(14)(15). Furthermore, the transferred MHC:OVA peptide complexes were functional in that they stimulated OVA-specific CD8 + T cell proliferation and IL-2 production (9).…”

Unique patterns of CD8+ T-cell-mediated organ damage in the Act-mOVA/OT-I model of acute graft-versus-host disease

“…However, as major allele (MHC) disparities are generally avoided in human clinical aHSCT, several murine models have been developed in that multiple minor allele disparities are present only [11][12][13]. Finally, a few novel murine aGVHD models have also been introduced based on single, well-defined minor histocompatibility allele recognized by a single, transgenic TCR present on all graft T cells, too [14][15][16].…”