The concept of heterologous immunity describes a phenomenon in which pathogen-elicited memory T cells, by virtue of the inherent cross-reactivity of T cell receptors (TCR), can recognize and respond to alloantigen and mediate destruction of transplanted tissue (1). This process is well-established in experimental rodent models of transplantation, and studies of human T cells have also identified several viral-specific T cell clones that have been shown both biochemically and functionally to cross-react with specific peptide:allo-MHC complexes (2). However, in vivo evidence that these virally-elicited allo-crossreactive memory T cells play a role in the donor-reactive immune response following clinical transplantation was lacking. In this issue of the AJT, Heutinck et al. report the first ex vivo analyses of virus-specific T cells possessing cross-reactivity to donor peptide:MHC in a cohort of renal allograft recipients (3). Their findings indicate that the presence of allo-cross reactive T cells was common, with about half (13 of 25) of transplant recipients demonstrating reactivity to donor antigen within the populations of T cells specific for viral epitopes. This number matches the previous study by Heemskerk and colleagues in which 45% of virus-specific CD8+ T cell clones isolated from normal healthy controls exhibited allo-crossreactivity against at least one HLA antigen in vitro (4), and highlights the fact that transplant recipients, who may have altered immune status due to the presence of chronic kidney disease, autoimmunity, etc., are not any more or less likely to possess allo-cross-reactive T cells relative to healthy individuals.
Interestingly, while these donor cross-reactive T cells were readily identified in the first few weeks following transplantation, longitudinal analyses failed to detect them in later months, time points at which alloreactive T cells specific for third-party antigens were still readily detectable. These intriguing results demonstrate that virus-specific donor cross-reactive T cells likely encounter graft-derived antigens, and that this population is modified by the presence of the graft. However, the fate of these cells in vivo following transplantation for the moment remains a mystery—do they become exhausted or senescent and undergo deletion? Are they differentially affected by immunosuppressive regimens? Or is their absence in the circulation at later time points explained simply by their propensity to migrate to and be retained within the graft itself?
The authors suggest that their data argues against the idea that continued exposure to donor-derived cross-reactive antigen drives exhaustion or senescence, based on their findings that cross-reactive T cells responded well to ex vivo peptide antigen stimulation both prior to and at early time points following transplantation (3). Still, T exhaustion takes time to develop and thus the possibility remains that exposure to a relatively high antigen load (i.e. the graft) drives T cell deletion in the long run. Evidence also exists to support the notion that cross-reactive T cells are differentially affected by immunosuppression, as work from our group has shown that T cells recognizing peptide:MHC ligands of altered affinity are differentially susceptible to immunosuppression in mouse models of transplantation. However, Heutinck et al. favor the hypothesis that donor cross-reactive T cells disappear from the circulation because they accumulate within the allograft; future prospective studies in which graft tissue is sampled with protocol biopsies will likely resolve this issue. One curious aspect that seems to argue against sequestration in the graft as the sole cause of the loss of cells from the circulation is the finding that donor cross-reactive cells were also not expanded following episodes of systemic viral reactivation, a situation in which viral antigen would be present systemically and should drive expansion of T cells in the circulation.
Clearly the most compelling question addressed by this study was the impact of donor cross-reactive T cells on graft rejection in vivo. Surprisingly, the data reveal that the presence of donor cross-reactive T cells in the circulation of renal transplant recipients was not associated with inferior outcomes relative to patients who lacked these cells. The findings corroborate an earlier study in lung allograft recipients, which found that recipients possessing donor cross-reactive T cells did not exhibit worse clinical outcomes relative to those that did not possess cross-reactive cells (5). However, many studies in both animal and human samples suggest that the overall frequency of donor-reactive memory T cells prior to transplantation increases the risk of rejection and poses a formidable barrier to tolerance induction. Thus, while these studies show that, on the whole, memory T cell populations that recognize donor antigen are bad for graft outcomes, the detailed work presented by Heutinck et al. tell us that not all T cell specificities that react with donor antigen in vitro are capable of carrying out allograft rejection in vivo. The reasons underlying this are likely multifactorial, and include the degree of cross-reactivity between the viral -and allo-antigen (i.e. TCR affinity) and whether or not the particular allo-MHC:peptide complex recognized by the virus-specific T cell is expressed within the kidney. Work aimed at the determining the characteristics of memory T cells that portend worse outcomes in vivo will advance the field and could guide the development of memory T cell “biomarkers” to predict patient outcomes following transplantation.
Footnotes
Disclosure
The author has no conflicts of interest to disclose as described by the American Journal of Transplantation.
References
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