Selective targeting of human alloresponsive CD8+ effector memory T cells based on CD2 expression.
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(+) CD2(hi) CD28(-) 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.
Emory Transplant Center, Emory University, Atlanta, GA, USA.
D J
DJ
Lo
T A
TA
Weaver
L
L
Stempora
A K
AK
Mehta
M L
ML
Ford
C P
CP
Larsen
A D
AD
Kirk
D000069594:Abatacept; D000077944:Alefacept; D018801:CD2 Antigens / Q000096:biosynthesis; D018106:CD28 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007156:Immunologic Memory / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods; D016030:Kidney Transplantation / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
D018801:CD2 Antigens; D018106:CD28 Antigens; D016207:Cytokines; D018796:Immunoconjugates; D011993:Recombinant Fusion Proteins; D000069594:Abatacept; D000077944:Alefacept