Selective targeting of human alloresponsive CD8+ effector memory T cells based on CD2 expression

D. J. Lo, T. A. Weaver, L. Stempora, A. K. Mehta, M. L. Ford, C. P. Larsen, A. D. Kirk

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

Abstract

Costimulation blockade (CoB), specifically CD28/B7 inhibition with belatacept, is an emerging clinical replacement for calcineurin inhibitor-based immunosuppression in allotransplantation. However, there is accumulating evidence that belatacept incompletely controls alloreactive T cells that lose CD28 expression during terminal differentiation. We have recently shown that the CD2-specific fusion protein alefacept controls costimulation blockade-resistant allograft rejection in nonhuman primates. Here, we have investigated the relationship between human alloreactive T cells, costimulation blockade sensitivity and CD2 expression to determine whether these findings warrant potential clinical translation. Using polychromatic flow cytometry, we found that CD8+ effector memory T cells are distinctly high CD2 and low CD28 expressors. Alloresponsive CD8+CD2hiCD28- T cells contained the highest proportion of cells with polyfunctional cytokine (IFNγ, TNF and IL-2) and cytotoxic effector molecule (CD107a and granzyme B) expression capability. Treatment with belatacept in vitro incompletely attenuated allospecific proliferation, but alefacept inhibited belatacept-resistant proliferation. These results suggest that highly alloreactive effector T cells exert their late stage functions without reliance on ongoing CD28/B7 costimulation. Their high CD2 expression increases their susceptibility to alefacept. These studies combined with in vivo nonhuman primate data provide a rationale for translation of an immunosuppression regimen pairing alefacept and belatacept to human renal transplantation. The authors show that alloresponsive memory T cells, particularly those resistant to costimulation blockade, can be selectively inhibited in vitro by targeting CD2, a molecule enriched on the surface of effector and memory T cells. See editorial by Farber on page 8.

Original languageEnglish
Pages (from-to)22-33
Number of pages12
JournalAmerican Journal of Transplantation
Volume11
Issue number1
DOIs
StatePublished - Jan 2011
Externally publishedYes

Keywords

  • Allotransplantation
  • co-stimulation blockade
  • memory CD8 T cells

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