T-lymphocyte tyrosine hydroxylase regulates T(H)17 T-lymphocytes during repeated social defeat stress

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder which results in deleterious changes to psychological and physical health. Patients with PTSD are especially susceptible to life-threatening co-morbid inflammation-driven pathologies, such as autoimmunity, while also demonstrating increased T-helper 17 (T(H)17) lymphocyte-driven inflammation. While the exact mechanism of this increased inflammation is unknown, overactivity of the sympathetic nervous system is a hallmark of PTSD. Neurotransmitters of the sympathetic nervous system (i.e., catecholamines) can alter T-lymphocyte function, which we have previously demonstrated to be partially mitochondrial redox-mediated. Furthermore, we have previously elucidated that T-lymphocytes generate their own catecholamines, and strong associations exist between tyrosine hydroxylase (TH; the rate-limiting enzyme in the synthesis of catecholamines) and pro-inflammatory interleukin 17A (IL-17A) expression within purified T-lymphocytes in a rodent model of psychological trauma. Therefore, we hypothesized that T-lymphocyte-generated catecholamines drive T(H)17 T-lymphocyte polarization through a mitochondrial superoxide-dependent mechanism during psychological trauma. To test this, T-lymphocyte-specific TH knockout mice (TH(T-KO)) were subjected to psychological trauma utilizing repeated social defeat stress (RSDS). RSDS characteristically increased tumor necrosis factor-α (TNFα), IL-6, IL-17A, and IL-22, however, IL-17A and IL-22 (T(H)17 produced cytokines) were selectively attenuated in circulation and in T-lymphocytes of TH(T-KO) animals. When activated ex vivo, secretion of IL-17A and IL-22 by TH(T-KO) T-lymphocytes was also found to be reduced, but could be partially rescued with supplementation of norepinephrine specifically. Interestingly, TH(T-KO) T-lymphocytes were still able to polarize to T(H)17 under exogenous polarizing conditions. Last, contrary to our hypothesis, we found RSDS-exposed TH(T-KO) T-lymphocytes still displayed elevated mitochondrial superoxide, suggesting increased mitochondrial superoxide is upstream of T-lymphocyte TH induction, activity, and T(H)17 regulation. Overall, these data demonstrate TH in T-lymphocytes plays a critical role in RSDS-induced T(H)17 T-lymphocytes and offer a previously undescribed regulator of inflammation in RSDS.