Contribution of direct and indirect recognition pathways to T cell alloreactivity.

Abstract

T cells from an HLA-DR11/DR12 responder were stimulated in mixed lymphocyte culture with cells carrying the DR1 antigen. After priming, T cells proliferated in response to both DR1-positive-stimulating cells and a peptide derived from a polymorphic region of the HLA-DR beta 1*0101 chain presented by responder's antigen-presenting cells (APC). The dominant epitope recognized by the primed T cells corresponded to residue 21-42 and was presented by the responder's HLA-DR12 antigen. The DR1 peptide-reactive T cells express T cell receptor V beta 3. The results demonstrate that allopeptides derived from the processing and presentation of donor major histocompatibility complex molecules by host-derived APC trigger alloreactivity. The frequency of T cells engaged in the indirect pathway of allorecognition is about 100-fold lower than that of T cells participating in the direct recognition of native HLA-DR antigen. However, indirect allorecognition may play an important role in chronic allograft rejection, a phenomenon that is mediated by the activation of T helper cells and of alloantibody- producing B cells.

Primed Allospecific T Cells Prevent the Effects of Costimulatory Blockade on Prolonged Cardiac Allograft Survival in Mice

“…B10.A heart graft rejection also resulted in an increase in the frequency of IFN-g-producing T cells specific for I-Ap and for B10.A sonicates (but not third party SJL sonicates) compared with T cells from naïve mice (no detectable indirect response was noted in naïve animals), demonstrating anticipated priming through the indirect pathway ( Figure 2). The numbers of indirectly primed T cells in mice that rejected heart grafts (ϳ130/million IFN-g producers vs. Ͻ 10/million in naïve animals) represented 5-10% of the total alloreactive T-cell repertoire, similar to previously reported studies by this laboratory and by other groups (23,27). No IL-4-or IL-5-producing alloreactive T cells specific for directly or indirectly presented alloantigens were detectable in any of these groups of animals (data not shown).…”

Use of Rapamycin Slows Progression of Cardiac Transplantation Vasculopathy

“…Direct allorecognition is the primary immunologic pathway responsible for acute cellular rejection early after organ transplantation. The indirect pathway of CD4 T-cell activation assumes an increasingly important role over time, 26 results in expansion of T-cell clones with specificity for multiple HLA-DR allopeptides presented by self-antigen presenting cells, and correlates closely with onset of chronic allograft rejection. [27][28][29] Since the indirect T-cell activation pathway gives rise to B-cell activation, development of anti-HLA IgG antibodies to the graft has been shown to be predictive of the development of graft atherosclerosis.…”

Immunosuppression for lung transplantation

“…In the immediate post-transplant period, there are many viable donor APCs in the graft, available for direct recognition by recipient T cells. These donor APCs (expressing allogeneic MHC class II antigens) and the high precursor frequency of recipient T cells capable of recognizing allo-MHC molecules without the requirement of priming make the direct alloresponse the dominant mode of immune recognition underlying AR (7). In fact, in a recent murine study where donor-type APCs were replaced by recipienttype APCs by bone marrow transplantation prior to allografting, AR was markedly attenuated, while CR persisted (8).…”