Despite encouraging results using lymphocyte function antigen-1 (LFA-1) blockade to inhibit BM and solid organ transplantation rejection in nonhuman primates and humans, the precise mechanisms underlying its therapeutic potential are still poorly understood. Using a fully allogeneic murine transplantation model, we assessed the relative distribution of total lymphocyte subsets in untreated versus anti-LFA-1-treated animals. Our results demonstrated a striking loss of naive T cells from peripheral lymph nodes, a concomitant gain in blood after LFA-1 blockade, and a shift in phenotype of the cells remaining in the node to a CD62L lo CD44 hi profile. We determined that this change was due to a specific enrichment of activated, graft-specific effectors in the peripheral lymph nodes of anti-LFA-1-treated mice compared with untreated controls, and not to a direct effect

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Donor-reactive memory T cells (Tmem) can play an important role in mediating graft rejection after transplantation. Transplant recipients acquire donor-reactive Tmem not only through prior sensitization with alloantigens but also through previous exposure to environmental pathogens that are cross-reactive with allogeneic peptide–MHC complexes. Current dogma suggests that most, if not all, Tmem responses are independent of the requirement for CD28 and/or CD154/CD40-mediated costimulation to mount a recall response. However, heterogeneity among Tmem is increasingly being appreciated, and one important factor known to impact the function and phenotype of Ag-specific T cell responses is the amount/duration of Ag exposure. Importantly, the impact of Ag exposure on development of costimulation independence is currently unknown. In this study, we interrogated the effect of decreased Ag amount/duration during priming on the ability of donor-reactive Tmem to mediate costimulation blockade-resistant rejection during a recall response after transplantation in a murine model. Recipients possessing donor-reactive Tmem responses that were generated under conditions of reduced Ag exposure exhibited similar frequencies of Ag-specific T cells at day 30 postinfection, but, strikingly, failed to mediate costimulation blockade-resistant rejection after challenge with an OVA-expressing skin graft. Thus, these data demonstrate the amount/duration of Ag exposure is a critical factor in determining Tmem’s relative requirement for costimulation during the recall response after transplantation.

Effector and memory T cells may cross-react with allogeneic antigens to mediate graft rejection. While the costimulation properties of Th1 cells are well studied, relatively little is known about the costimulation requirements of microbe elicited Th17 cells. The costimulation blocker CTLA-4 Ig has been ineffective in the treatment of several Th17 driven autoimmune diseases and is associated with severe acute rejection following renal transplantation, leading us to investigate whether Th17 cells play a role in CD28/CTLA-4 blockade resistant alloreactivity. We established an antigen-specific model in which Th1 and Th17 cells were elicited via Mycobacterium tuberculosis (M.Tb) and Candida albicans (Candida) immunization, respectively. Candida immunization elicited a higher frequency of Th17 cells and conferred resistance to costimulation blockade following transplantation. Compared to the M.Tb group, Candida elicited Th17 cells contained a higher frequency of IL-17+IFN-γ+ producers and a lower frequency of IL-10+ and IL-10+IL-17+ cells. Importantly, Th17 cells differentially regulated the CD28/CTLA-4 pathway, expressing similarly high CD28 but significantly greater amounts of CTLA-4 compared to Th1 cells. Ex vivo blockade experiments demonstrated that Th17 cells are more sensitive to CTLA-4 coinhibition and therefore less susceptible to CTLA-4 Ig. These novel insights into the differential regulation of CTLA-4 coinhibition on CD4+ T cells have implications for the immunomodulation of pathologic T cell responses during transplantation and autoimmunity.

Background Blockade of costimulatory molecules is a potent method of inducing long-term graft survival. We have previously addressed the issue of donor-reactive T cell precursor frequency on relative costimulation dependence, and found that the presence of a high precursor frequency of donor-reactive CD8+ T cells resulted in costimulation blockade-resistant graft rejection, whereas the presence of a low-frequency donor-reactive population did not. To address the mechanisms by which high frequency T cells obviated the requirement for costimulation, we asked whether a low frequency population responding concomitantly with a high frequency response also demonstrated costimulation independence. Methods A model system was established in which B6 mice containing a low frequency of anti-mOVA responders and a high frequency of anti-BALB/c responders received a skin graft from B6.mOVAxBALB/c F1 donors in the presence or absence of CTLA-4 Ig/anti-CD154 costimulatory blockade. Results Results revealed that in the presence of costimulation blockade, high frequency anti-BALB/c T cells augmented the effector activity of low frequency anti-mOVA T cells, but did not enhance the accumulation of anti-mOVA T cells capable of mediating graft rejection. Conclusions These results demonstrate that both antigen-specific and antigen-independent factors contribute to the relative costimulation-independence of high frequency T cell responses.