CD8+ T Cells Differentiate into a Potent CD43+ Effector Population During Acute Allograft Rejection

Abstract

Abstract Although acute rejection threatens allograft function, little is known about the functional properties of graft-specific effector CD8 +T cells. Using the Balb/c H-2L(d) into C57Bl/6 H-2(b) fully allogeneic skin graft model, we identified host CD8 +T cells specific for the L(d) QL9 epitope using MHC tetramers. L(d) QL9 +T cells increased in number and differentiated into CD44 +effector populations by day 10 post-graft with Balb/c skin, but not third-party C3H skin. Using dimensionality reduction analysis, we found that a population of CD62L loeffector CD8 +T cells expressing the surface receptor CD43 formed during graft rejection in the draining lymph nodes, spleen, and blood. The frequency of CD43 +effectors peaked from day 10–14 post-graft, indicative of a short-lived population. CD43 +CD8 +T cells displayed potent effector functions relative to CD43 −cells, including Granzyme B expression, IFN-γ/TNF-α co-production, and accelerated Balb/c graft rejection (p<0.01 for each). Adoptive transfer experiments revealed that only 31% of the L(d) QL9 +T cells divided on day 14 post-graft, versus 95.6% of OT-I T cells after mOVA skin grafting. CD43 expression was only expressed on cells in their final division. Finally, we rechallenged flow cytometry purified CD45.1 CD43 +and CD43 −effector CD8 +T cells with a Balb/c skin graft, and found that approximately half of the CD43 −population became CD43 +, while all of the CD43 +population remained CD43 +on day 21 (49% vs 96%, p<0.001). Together, these data demonstrate that CD8 +T cells differentiate into a CD43 +population after grafting that undergoes weak proliferation and yet is functionally potent.