Transplant recipients harbor immunity to vaccines and pathogens (e.g. CMV, EBV). Pre-existing immunity can have significant antigen-specific ramifications, usually attributed to heterologous immunity, as pathogen-reactive T cells that are cross-reactive to donor MHC. However, we find that vaccine-induced immunity that lacks donor reactivity can unexpectedly and covertly block allograft tolerance induction. We show that this 'incognito' blockade of tolerance requires donor-derived cells that simultaneously express and thereby “link” donor MHC and vaccine-associated antigens (“linked antigens”; e.g. donor cells infected with CMV or EBV). 'Incognito' memory further depends on vaccine-reactive memory CD8+ T cells, and not pre-existing antibody, to drive alloreactive immunity. We immunized C57BL/6 (H-2Kb) mice with an adjuvant and ovalbumin (OVA). The vaccination generated strong OVA-specific host T cell memory and antibodies with limited cross-reactivity to donor-derived BALB/c (H-2Kd) cells. OVA-immune mice were transplanted with BALB/c pancreatic islet cells and treated with anti-CD154 and BALB/c donor-specific transfusion (DST). When donor cells only expressed donor MHC (i.e. BALB/c DST), OVA-specific memory did not inhibit allograft tolerance induction relative to control animals. However, when donor cells simultaneously expressed vaccine-associated OVA and donor BALB/c antigens (i.e. BALB/c-OVA DST), these “linked antigens” readily disrupted tolerance in 10/11 OVA-immune mice (p=.0005 vs controls). Next, we determined the specific components of pre-existing immunity that were necessary for 'incognito' perturbation of tolerance. C57BL/6 mice were depleted of either CD8+ T cells or CD4+ T cells prior to immunization with adjuvant and OVA. CD8-depleted vaccinated mice generated OVA-specific antibodies (but not memory CD8+ T cells), and yet did not block allograft tolerance in response to BALB/c-OVA DST. However, CD4-depleted vaccinated mice, which had generated OVA-reactive memory CD8+ T cells but not antibodies, potently blocked tolerance in 7/7 OVA-immune mice (p=.01 vs controls). Thus, our data suggest remarkable implications for pathogen-immune recipients of donor grafts that express pathogen-associated antigens: Immunity that lacks substantial pre-existing donor reactivity can still harbor 'incognito' CD8+ T cell memory that potently impairs tolerance after exposure to pathogen-infected donor cells.

« Back to 2015 American Transplant Congress