Systemic Cancer Immunostimulatory Therapies and Acute Viral Infection Induce Corticosteroid-Mediated Thymic Involution and Naïve T cell Output in Mice and Humans

Abstract

Abstract Thymic involution (TI) occurs with aging and during stress responses, decreasing naïve T cell output. Thymic progenitor apoptosis can occur directly by corticosteroids (CS) leading to transient involution followed by recovery. The effects of systemic immunotherapies (IT) used in cancer or immune stimulation via acute viral infection on the thymus has not been well-characterized and was the primary goal of this study. IT treatment of mice with high dose IL-2 (HD IL-2) or models of acute viral infection (mouse cytomegalovirus, MCMV) all resulted in rapid TI due to apoptosis of CD4/CD8 double-positive progenitors followed with a reduction in naïve T cell content. Interestingly, cessation of therapy or resolution of viral infection resulted in greater thymic size compared to untreated recipients, indicating a rebound effect. In both models, increased CS levels in the serum of mice preceded TI. Clinically, patients receiving HD IL-2 for cancer had significantly reduced T cell receptor excision circles, a marker for naïve T cell output, also correlating with increased cortisol levels. Using a model of sub-lethal MCMV infection that did not increase systemic pro-inflammatory cytokines, we observed a similar correlation of TI and increased CS levels. To further analyze the effects of CS on TI, mice were adrenalectomized and then given HD IL-2, where significantly reduced CS levels correlated with partial protection from TI. These results indicate that strong systemic immunostimulation by either IT or acute viral infections markedly induce transient CS-mediated TI, leading to a decrease in naïve T cells. Therefore, targeting CS responses in preventing TI and, especially with the aged, allow for naïve T cell populations to be maintained.