Impact of infection on transplantation tolerance

Abstract

Allograft tolerance is the ultimate goal of organ transplantation. Current strategies for tolerance induction mainly focus on inhibiting alloreactive T cells while promoting regulatory immune cells. Pathogenic infections may have direct impact on both effector and regulatory cell populations, therefore can alter host susceptibility to transplantation tolerance induction as well as impair the quality and stability of tolerance once induced. In this review, we will discuss existing data demonstrating the effect of infections on transplantation tolerance, with particular emphasis on the role of the stage of infection (acute, chronic, or latent) and the stage of tolerance (induction or maintenance) in this infection-tolerance interaction. While the deleterious effect of acute infection on tolerance is mainly driven by proinflammatory cytokines induced shortly after the infection, chronic infection may generate exhausted T cells that could in fact facilitate transplantation tolerance. In addition to pathogenic infections, commensal intestinal microbiota also has numerous significant immunomodulatory effects that can shape the host alloimmunity following transplantation. A comprehensive understanding of these mechanisms is crucial for the development of therapeutic strategies for robustly inducing and stably maintaining transplantation tolerance while preserving host anti-pathogen immunity in clinically relevant scenarios.

Keywords: T cells; co-stimulation blockade; donor negative vaccine; infections; intestinal microbiota; regulatory immune cells; transplantation tolerance.

Figure 1.. Effects of infection on alloreactive T cell activation.

Activation of alloreactive T cells require 3 signals: TCR engagement, costimulation, and inflammatory cytokines. These three signals can be altered by infections: pathogen-specific T cells have the potential to cross-react with alloantigens presented by host APCs and become activated to attack the allograft. IL-2 generated during an infection can augment the costimulation signal through inhibiting the expression of anergy-related genes. Type-I IFN and IL-12 induced by infections can bind to their receptors on T cells and serve as the third signal.

Fig. 2.. Effects of infection on the regulatory immune cell network.

CD4⁺Foxp3⁺ Tregs play a central role in the regulatory immune cell network. Tregs inhibit the effector T cells (Teffs) through a number of mechanisms including the production of IL-10, TGF-β, and IL-35. Tregs are also important for the expansion and/or maintenance of other regulatory cell populations, including Tol-DCs, Mreg and MDSCs. These regulatory cell populations are themselves capable of directly suppressing Teffs via several unique mechanisms. During an infection, the induced inflammatory cytokines can disrupt this network, block the suppressive function of various regulatory cell populations, and/or promote their differentiation to inflammatory immune cells.

Fig. 3.. Impact of infection on transplantation tolerance.

The impact of infection on transplantation tolerance varies according to the acuity of the infection. Generally, acute infections readily prevent the induction of tolerance but slowly erode established tolerance. On the contrary, chronic infections may facilitate transplantation tolerance due to populations of exhausted T cells generated under persistent chronic pathogen stimulation. Latent infection and transplantation tolerance have reciprocal effects on each other. Tolerance may permit reactivation of latent infections but prevent their dissemination, whereas reactivation of latent infections may impair the induction of transplantation tolerance.