Disruption of Transplant Tolerance by an “Incognito” Form of CD8 T Cell–Dependent Memory

Abstract

Several approaches successfully achieve allograft tolerance in preclinical models but are challenging to translate into clinical practice. Many clinically relevant factors can attenuate allograft tolerance induction including intrinsic genetic resistance, peri-transplant infection, inflammation, and pre-existing anti-donor immunity. The prevailing view for immune memory as a tolerance barrier is that the host harbors memory cells that spontaneously cross-react to donor MHC antigens. Such pre-existing ‘heterologous’ memory cells have direct reactivity to donor cells and resist most tolerance regimens. In this study, we developed a model system to determine if an alternative form of immune memory could also block tolerance. We posited that host memory T cells could potentially respond to donor-derived non-MHC antigens, such as latent viral antigens or autoantigens, to which the host is immune. Results show that immunity to a model non-self antigen, ovalbumin (OVA), can dramatically disrupt tolerance despite undetectable initial reactivity to donor MHC antigens. Importantly, this blockade of tolerance was CD8 T cell-dependent and required linked antigen presentation of alloantigens with the test OVA antigen. As such, this pathway represents an unapparent, or ‘incognito,’ form of immunity that is sufficient to prevent tolerance and that can be an unforeseen additional immune barrier to clinical transplant tolerance.

Characterization of eomesodermin and T-bet expression by allostimulated CD8+ T cells of healthy volunteers and kidney transplant patients in relation to graft outcome

“…Allo‐reactive Tmem constitute a major barrier to improved long‐term organ allograft survival , where impairment of Tmem responses is crucial to attain Ag‐specific tolerance . T cell depletion is a common induction therapy in tx protocols.…”

Diverse Routes of Allograft Tolerance Disruption by Memory T Cells

“…As such, the importance of assessing preexisting humoral or cellular immunity to donor MHC has been a major focus of screening efforts in transplantation (40)(41)(42). While such efforts are clearly warranted, there are potentially alternative routes whereby T cell memory could impair tolerance induction without a requirement for substantial heterologous immunity to the donor MHC (43). Unfortunately, the metagenome of both organ donors and recipients encode a variety of non-self antigens, such as those derived from microbiota (44,45) or from latent infections such as CMV and EBV (46)(47)(48)(49) that are clearly associated with impaired allograft outcomes in clinical transplantation.…”

“…This problem of donor-derived, non-self, non-MHC antigens has arguably been under-represented in most small animal studies. This being the case, we developed a model system in which the donor expressed a non-self transgenic antigen (OVA) to which the host was immune via vaccination ( 43 ), a scenario that could have relevance to clinical transplantation in which vaccination might protect from a donor-derived pathogen ( 54 ). Tolerance was induced using a common approach of administering a pre-transplant donor-specific transfusion (DST) in the form of donor spleen cells plus costimulation blockade ( 55 , 56 ).…”

Memory T‐cell exhaustion and tolerance in transplantation

“…In brief, incognito memory arises when the host antigen-presenting cell (APC) presents both alloantigen and a microbe-derived antigen for which the host possesses antigen-specific memory T cells ( Figure 1F). 30 This mechanism seems to be most relevant for memory cells that are specific for vaccine-derived antigens or antigens from latent infections such as EBV and CMV. Essentially, this pathway is the opposite of the mechanism of linked suppression identified by Waldmann in the early 1990s.…”

“…Importantly, this disruption of tolerance was independent of TCR cross-reactivity. 30 This mechanism seems to be most relevant for memory cells that are specific for vaccine-derived antigens or antigens from latent infections such as EBV and CMV.…”