Association of Autophagy in the Cell Death Mediated by Dihydrotestosterone in Autoreactive T Cells Independent of Antigenic Stimulation

Abstract

Gender disparity is well documented in the mouse model of experimental autoimmune encephalomyelitis (EAE) induced with proteolipid protein (PLP) 139-151, in which female, but not male, SJL mice show a chronic relapsing-remitting paralysis. Furthermore, dihydrotestosterone (DHT) has been shown to ameliorate the severity of EAE, but the underlying mechanisms of its protective effects are unclear. Using major histocompatibility complex (MHC) class II dextramers for PLP 139-151, we tested the hypothesis that DHT selectively modulates the expansion and functionalities of antigen-specific T cells. Unexpectedly, we noted that DHT induced cell death in antigen-specific, autoreactive T cells, but the effects were not selective, because both proliferating and non-proliferating cells were equally affected independent of antigenic stimulation. Furthermore, DHT-exposed PLP 139-151-specific T cells did not show any shift in cytokine production; rather, frequencies of cytokine-producing PLP-specific T cells were significantly reduced, irrespective of T helper (Th) 1, Th2, and Th17 subsets of cytokines. By evaluating cell death and autophagy pathways, we provide evidence for the induction of autophagy to be associated with cell death caused by DHT. Taken together, the data provide new insights into the role of DHT and indicate that cell death and autophagy contribute to the therapeutic effects of androgens in autoreactive T cells.

Mechanisms of sex hormones in autoimmunity: focus on EAE

“…Our observation that DHT induces cell death of both proliferating and non-proliferating T cells may mean that the DHT-mediated effects might have occurred due to cell death. Importantly, we have also demonstrated that cell death can occur in conjunction with autophagy in DHT-treated cells [161], suggesting that common signaling cascades, or crosstalk, may exist between the two processes. Although dissecting this complexity is a challenge, using model systems that are deficient for apoptosis and autophagy machineries, such as caspase-3-and ATG-deficient mice, may be helpful.…”

Branched chain α‐ketoacid dehydrogenase kinase 111–130, a T cell epitope that induces both autoimmune myocarditis and hepatitis in A/J mice

“…All sections were examined by a board‐certified pathologist blinded to treatment. The total number of inflammatory cell foci was determined as reported previously . For evaluation of inflammatory foci in the livers, stained sections were scanned with the aid of Aperio digital pathology slide scanners (Leica Biosystems, Wetzlar, Germany).…”

“…Mechanistically, autoimmune responses against cardiac antigens are believed to mediate the development of DCM, as sera from DCM patients have been shown to contain autoantibodies for cardiac antigens, such as cardiac myosin, and cardiac troponin-I (cTnI) [3][4][5][6][7]. Recently, we demonstrated that the mitochondrial inner membrane protein, adenine nucleotide translocator 1 (ANT 1 ) can be a target autoantigen in the pathogenesis of DCM by identifying ANT 1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] as the disease-inducing epitope in A/J mice [2]. In this report, we describe the potential relevance of the mitochondrial matrix branched chain a-ketoacid dehydrogenase (BCKD) complex proteins to myocarditis and hepatitis.…”

Androgen-Induced Immunosuppression

“…Postpubescent gonadectomized male mice exhibit larger peripheral lymphoid organs housing a greater number of lymphocytes, including both CD4+ and CD8+ T cells ( 92 , 99 ). The expansion of peripheral lymphoid organs after the removal of androgens may be related to increases in thymic output and/or lessened peripheral T cell death, as an in vitro study recently demonstrated that DHT can non-selectively induce cell death in peripheral T cells ( 100 ).…”