The Allo- and Viral-Specific Immunosuppressive Effect of Belatacept, but Not Tacrolimus, Attenuates With Progressive T Cell Maturation

Abstract

Tacrolimus impairs allo- and viral-specific T cell responses. Belatacept, a costimulation-based alterative 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 seronegative (n=10) volunteers were studied using flow cytometry, interrogating proliferation (CFSE 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 IFN-γ, TNF-α, 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 allospecific 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.

Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates

“…However, this was not the case using an antagonist of CD80/86 (CTLA4-Ig), which inhibits similarly naive and memory T cell proliferation stimulated with alloantigens but not when stimulated with viral peptides. This is in accordance with a recent study reporting that CTLA4-Ig efficiency decreased in increasingly matured human T cells when stimulated with a CMV peptide or alloantigens (30). Collectively, our results suggest that human memory T cell reactivation in vitro is still CD28-dependent but tightly controlled by CTLA-4 and/or PD-L1 coinhibitory signals as described in mouse models of candida or Listeria monocytogenes infection (31,32).…”

Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients

“…However, following depletion we observed a dramatic shift of expression from memory to naïve that persisted throughout reconstitution. Furthermore, these repopulating naïve cells expressed CD28 and therefore were susceptible to costimulation blockade (8, 10) , supporting this as a mechanism for the efficacy of this regimen. Practically, this introduces a method to formally assess the dynamic period of post-depletional repopulation, and we would suggest that Ki67 measurement be considered as a mechanistic adjunct to studies involving vigorous induction therapy, particularly when subsequent immunosuppressive minimization is concerned.…”

“…PBMCs were stimulated with CD3-depleted PBMCs from either the original kidney donors, HLA-mismatched third-party allo-donors, CMV-pp65 peptides, or EBV proteins and interrogated by intracellular cytokine staining (ICCS). Previous studies have demonstrated that multi-cytokine producing T cells respond more vigorously to specific antigens when compared with single-cytokine producers (8, 10, 31-32) . We therefore applied the definition of a TNF-α/IFN-γ/IL-2 triple cytokine producing T cell as a significant responder to antigen stimulation.…”

“…T cell–mediated responses to specific allo-donors or HLA-mismatched third-party donors were evaluated using the method described previously (8, 10, 19) . Briefly, recipient’s PBMCs were exposed to irradiated allo-stimulator PBMCs isolated from specific donors and HLA-mismatched third-party donors.…”

CD28 Negative T Cells: Is Their Loss Our Gain?

“…Indeed, it has been recently shown that belatacept’s immunosuppressive effect, in contrast to that of tacrolimus, weakens with increasingly matured effector cells. 4 Although costimulation blockade-based immunotherapies boast superior side effect profiles compared to calcineurin inhibitor-based therapies, 3 overcoming the CoBRR hurdle is critical to their generalized use. This review will focus on CD28 loss in humans unless otherwise noted.…”