Donor-reactive T-cell stimulation history and precursor frequency: barriers to tolerance induction

Abstract

Blockade of T-cell costimulatory pathways represents a potent and specific method of preventing naïve antidonor T-cell responses after transplantation in mouse, monkey, and man. However, numerous studies have shown that the presence of donor-reactive memory T cells in the recipient poses a sometimes insurmountable barrier to long-term graft survival and tolerance induction. Here, we discuss the ways in which donor-reactive memory T cells may arise from environmental exposure to pathogens. Pathogen-specific memory T cells, by virtue of the inherent degeneracy of T-cell receptor recognition of peptide:major histocompatibility complex ligands, may exhibit cross reactivity with allogeneic peptide:major histocompatibility complexes and thereby mediate graft rejection. From the recent explosion in knowledge of the heterogeneity of memory T-cell resulting from variations in frequency and duration of antigen exposure, cytokine milieu, site of priming, and a host of other factors, it is becoming increasingly well appreciated that different memory T-cell populations may exhibit differential susceptibilities to tolerance induction. Thus, the immune history of a transplant recipient and frequencies of donor-cross-reactive memory T cells within the various compartments may dictate the likelihood of success or failure of tolerance induction.

Figure 1

Impact of antigen-specific T cell precursor frequency on susceptibility to costimulation blockade. A, Cells stimulated at low precursor frequency are required to undergo multiple rounds of division in order to generate a threshold number of effector cells needed to mediate graft rejection. B, Cells that undergo multiple rounds of division in the absence of costimulation fail to differentiate into competent effectors and undergo increased cell death at later rounds of division. C, In contrast, cells that are stimulated at high naïve T cell precursor frequency must undergo many fewer rounds of division in order to a sufficient number of effector cells to mediate graft rejection. D, Populations that had undergone fewer rounds of division in the absence of costimulation had better effector function and reduced death as compared to those that underwent more rounds of division in the absence of costimulation.