Impact of Human Mutant TGFβ1/Fc Protein on Memory and Regulatory T Cell Homeostasis Following Lymphodepletion in Nonhuman Primates

Abstract

Transforming growth factor β1 (TGFβ1) plays a key role in T cell homeostasis and peripheral tolerance. We evaluated the influence of a novel human mutant TGFβ1/Fc (human IgG4 Fc) fusion protein on memory CD4⁺ and CD8⁺ T cell (Tmem) responses in vitro and their recovery following antithymocyte globulin (ATG)-mediated lymphodepletion in monkeys. TGFβ1/Fc induced Smad2/3 protein phosphorylation in rhesus and human peripheral blood mononuclear cells and augmented the suppressive effect of rapamycin on rhesus Tmem proliferation after either alloactivation or anti-CD3/CD28 stimulation. In combination with IL-2, the incidence of CD4⁺ CD25^hi Foxp3^hi regulatory T cells (Treg) and Treg:Th17 ratios were increased. In lymphodepleted monkeys, whole blood trough levels of infused TGFβ1/Fc were maintained between 2 and 7 μg/mL for 35 days. Following ATG administration, total T cell numbers were reduced markedly. In those given TGFβ1/Fc infusion, CD8⁺ T cell recovery to predepletion levels was delayed compared to controls. Additionally, numbers of CD4⁺ CD25^hi CD127^lo Treg increased at 4-6 weeks after depletion but subsequently declined to predepletion levels by 12 weeks. In all monkeys, CD4⁺ CD25^hi Foxp3^hi Treg/CD4⁺ IL-17⁺ cell ratios were reduced, particularly after stopping TGFβ1/Fc infusion. Thus, human TGFβ1/Fc infusion may delay Tmem recovery following lymphodepletion in nonhuman primates. Combined (low-dose) IL-2 infusion may be required to improve the Treg:Th17 ratio following lymphodepletion.

Keywords: T cell biology; animal models: nonhuman primate; basic (laboratory) research/science; fusion proteins and monoclonal antibodies; immune regulation; immunobiology; immunosuppressant; immunosuppression/immune modulation; tolerance.