Contribution of direct and indirect recognition pathways to T cell alloreactivity

Abstract

SummaryT cells from an HLA-DRll/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-DRBI*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 V33. 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.T wo pathways of antigen recognition have been considered in T cell responses to MHC alloantigens (1-4). A direct pathway involves T cells capable of recognizing alloantigens as intact molecules on the surface of allogeneic stimulator cells. The TCRs recognize, in this case, unknown peptides bound in the groove of allogeneic MHC molecules and/or adjacent epitopes of the aUogeneic MHC molecule. The precursor frequency of T cells involved in the direct recognition pathway is extremely high, with estimates of 1-5% of T cells exhibiting blastogenic responses to allogeneicstimulating cells in MLC (2). There is ample evidence that the direct pathway of allorecognition is the principal contributor to antigraft cytotoxic T cell responses mediating early rejection episodes. The very high number of precursor T cells participating in direct aUorecognition has been attributed to molecular mimicry resulting from the engagement of TCRs whose innate reactivity was for a complex formed by a self-MHC molecule with an endogenous or exogenous peptide (5-9).The indirect pathways of allorecognition has come into focus more recently, with the realization that this pathway may explain T helper cell-dependent cytotoxic T cell and alloantibody responses (10-13). In this pathway, T cells recognize graft MHC alloantigens that have been processed and presented by host APC. Indirect recognition is restricted by the host MHC class II molecule, which has bound a peptide derived from the processing of an allogeneic MHC molecule that is, therefore, the classical pathway of conventional antigen recognition by CD4 T cells (10-16). The involvement of alloantigen-specific CD4 T helper cells, as mediators of alloantibody generation, suggests that the indirect pathway plays an essential role in chronic rejection, e.g., in the steady but continuous attrition (2-5%/yr) of organ allografts late after transplantation (17,18).In previous studies we have shown th...