Inability to Induce Tolerance Through Direct Antigen Presentation

Abstract

Both the direct and indirect antigen presentation pathways are important mechanisms for T cell-mediated allograft rejection. Studies using knockout mice and monoclonal antibodies have demonstrated that CD4π T cells are both necessary and sufficient for the rejection of allogeneic tissues, including skin, heart, and islet. Furthermore, combined blockade of the CD28/B7 and CD154/CD40 costimulatory pathways induces tolerance in multiple CD4π T-cell dependent allograft models. In this study, we addressed the T-cell requirement for costimulation in direct antigen presentation. We demonstrated that class II-specific alloreactive Tcell receptor transgenic T cells were sufficient to mediate allograft rejection independent of costimulatory blockade. Analysis of the costimulatory capacity of different antigen presenting cell (APC) populations demonstrated that APCs resident within the donor skin, Langerhans cells, are potent stimulators not requiring CD28-or CD154-dependent costimulation for direct major histocompatibility complex (MHC) antigen presentation. These results complement previous work examining the role of costimulation on CD8π T cells, supporting a model in which the effectiveness of costimulatory blockade in the setting of transplantation may be selective for the indirect pathway of MHC alloantigen presentation.

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

“…Our finding that primary CD4 + T-cell expansion in vivo was inhibited by CTLA4Ig is consistent with the reported effects of CTLA4Ig on T-cell proliferation using the OVA TCR-tg model (26). Furthermore, Rulifson et al (10) have recently demonstrated that in the ABM TCR-tg system combined anti-B7-1 mAb and anti-B7-2 mAb blockade inhibits TCR-tg CD4 + T-cell division in response to direct antigen presentation in vitro. Our results also provide further evidence for functional inhibition of alloantigen-reactive cells following CTLA4Ig administration in vivo.…”

“…Consequently, in vivo studies have been limited to using MHC class I-alloreactive TCR-tg systems in which the alloimmune response is mediated by CD8 + T cells (5)(6)(7)(8), or to using antigen-specific rather than allospecific CD4 + TCR-tg animals as surrogates (9). Recently, a novel TCR-tg MHC class II-alloreactive transplantation model has been described (10,11). The anti-bm12 (ABM) TCR-tg mouse (12) expresses a TCR that utilizes the Va2.1 and Vb8.1 chains and specifically recognizes the MHC class II molecule I-A bm12 found on B6.C-H2bm12/KhEg (bm12) mice.…”

“…More than 95% of peripheral CD4 + T cells in ABM mice express the Va2 + Vb8 + TCR, as assessed by flow cytometric analysis. I-A bm12 is the only histocompatibility mismatch between ABM and bm12 mice and is sufficient to elicit a vigorous H-2 b alloimmune response to bm12 both in vitro and in vivo (10)(11)(12). Here, we have developed a model system in which the fate of I-A bm12 -specific CD4 + T cells from ABM TCR-tg mice can be tracked following adoptive transfer into syngeneic C57BL/6 (B6) recipients transplanted with bm12 skin grafts expressing I-A bm12 .…”

Fundamental Immunology of Skin Transplantation and Key Strategies for Tolerance Induction

“…However, a recent study showed that LCs can induce T cells to reach an activation threshold that is sufficient for transplant rejection in the absence of a costimulatory signal or under the condition of impaired NF-jB pathway, which indicates that LCs can prime T cells through a bypass signal pathway (Molinero et al 2008;Rulifson et al 2002). This finding may explain why certain immune inhibitors, such as rapamycin, which target NF-jB, do not display the expected effects in skin transplantation models that have abundances of LCs (Sun et al 2008).…”

Immunological Considerations for Inducing Skin Graft Tolerance

“…This model was not associated with GVHD as measured by examination of intestines, liver, skin, or other tissues (Liu et al, 2007). Rulifson et al (2002) demonstrated that Langerhans cells resident in the skin of the donor were such effective antigen presenting cells (APCs) that they could prime T cells for activation independently of either the B7 or CD40 activation pathways. In their hands, the strength of this direct antigen presentation reaction limited the success of tolerance induction mediated through the interruption of either B7-CD28 or CD40-CD154 pathway.…”