The allo- and viral-specific immunosuppressive effect of belatacept, but not tacrolimus, attenuates with progressive T cell maturation

H. Xu*, S. D. Perez, J. Cheeseman, A. K. Mehta, A. D. Kirk

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Tacrolimus impairs allo- and viral-specific T cell responses. Belatacept, a costimulation-based alternative to tacrolimus, has emerged with a paradoxical picture of less complete control of alloimmunity with concomitant impaired viral immunity limited to viral-naïve patients. To reconcile these signatures, bulk population and purified memory and naïve lymphocytes from cytomegalovirus (CMV)-seropositive (n = 10) and CMV-seronegative (n = 10) volunteers were studied using flow cytometry, interrogating proliferation (carboxyfluorescein succinimidyl ester dilution) and function (intracellular cytokine staining) in response to alloantigens or CMV-pp-65 peptides. As anticipated, T cells from CMV-experienced, but not naïve, individuals responded to pp-65 with a small percentage of their repertoire (<2.5%) consisting predominantly of mature, polyfunctional (expressing interferon gamma, tumor necrosis factor alpha and IL-2) T effector memory cells. Both CMV naïve and experienced individuals responded similarly to alloantigen with a substantially larger percentage of the repertoire (up to 48.2%) containing proportionately fewer polyfunctional cells. Tacrolimus completely inhibited responses of CMV- and allo-specific T cells regardless of their maturation. However, belatacept's effects were decreasingly evident in increasingly matured cells, with minimal effect on viral-specific triple cytokine producers and CD28-negative allo-specific cells. These data indicate that belatacept's immunosuppressive effect, unlike tacrolimus's, wanes on progressively developed effector responses, and may explain the observed clinical effects of belatacept. The authors characterize CMV- and allo-specific memory T cells and show that belatacept has decreasing inhibitory effect on increasingly matured memory cells, and minimal effect on the most highly differentiated CMV- and allo-specific cells.

Original languageEnglish
Pages (from-to)319-332
Number of pages14
JournalAmerican Journal of Transplantation
Volume14
Issue number2
DOIs
StatePublished - Feb 2014
Externally publishedYes

Keywords

  • Belatacept
  • T cell maturation
  • calcineurin inhibitor
  • costimulation blockade
  • cytomegalovirus
  • memory T cells

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