T Cells Primed byLeishmania majorInfection Cross-React with Alloantigens and Alter the Course of Allograft Rejection

Abstract

Alloreactive T lymphocytes can be primed through direct presentation of donor MHC:peptide complexes on graft cells and through indirect presentation of donor-derived determinants expressed by recipient APCs. The large numbers of determinants on an allograft and the high frequency of the alloreactive repertoire has further led to speculation that exposure to environmental Ags may prime T cells that cross-react with alloantigens. We sought to develop a model in which to test this hypothesis. We found that CD4+ T cells obtained from C57BL/6 (B6) mice that clinically resolved Leishmania major infection exhibited statistically significant cross-reactivity toward P/J (H-2p) Ags compared with the response to other haplotypes. B6 animals that were previously infected with L. major specifically rejected P/J skin grafts with second set kinetics compared with naive animals. Although donor-specific transfusion combined with costimulatory blockade (anti-CD40 ligand Ab) induced prolonged graft survival in naive animals, the same treatment was ineffective in mice previously infected with L. major. The studies demonstrate that cross-reactive priming of alloreactive T cells can occur and provide direct evidence that such T cells can have a significant impact on the outcome of an allograft. The results have important implications for human transplant recipients whose immune repertoires may contain cross-reactively primed allospecific T cells.

Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help

“…Our current study explored a novel aspect of memory CD8 T cells, i.e., CD154 costimulation blockade-resistant activation. We and others (9,(33)(34)(35) have demonstrated that alloreactive CD8 T cells in the absence of CD4 help fail to develop this phenotype, as reactivation of helpless alloreactive CD8 memory T cells remains susceptible to the CD154 blockade suggesting that these cells are functionally naive.…”

Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

“…Experimental animal models have revealed that the exposure of hosts to viral or parasitic agents prior to transplantation can result in the development of memory T cells (5)(6)(7) that are resistant to the effects of anti-CD154 therapy (8,9). A subset of these pathogen-specific memory T cells has been shown to cross-react, by molecular mimicry, with alloantigen presented by donor or recipient MHC molecules (10).…”

Cross-immune tolerance: conception and its potential significance on transplantation tolerance

“…For example, mouse T-cell clones that are specific to poly(Glu60,Ala30,Tyr10), pigeon cytochrome c or sheep insulin can respond to a variety of allogeneic stimulator cells with a very high frequency (61% responded to at least one allogeneic haplotype, and 39% responded to more than one allogeneic stimulator). 1 In animal models, infection of B6 mice with Leishmania major can induce vigorous rejection of P/J skin allografts, 5 suggesting that T cells activated by the parasitic antigens can readily attack the skin allografts. Moreover, mice challenged with lymphocytic choriomeningitis virus prior to or concurrently with skin transplantation can significantly accelerate allograft rejection and prevent transplantation-tolerance induction.…”

“…Besides T cells that are intrinsically reactive to alloantigens, a considerable fraction of T cells that are programmed to respond to nominal antigens can also be crossreactive to alloantigens. [4][5][6] Importantly, recent studies have convincingly demonstrated that certain memory T cells that are specific to conventional pathogens are highly alloreactive in transplant models. 3 The crossreactive nature of alloreactive T cells clearly highlights the flexibility of T-cell receptors (TCR) in their recognition of transplant antigens.…”