BRAIN, BEHAVIOR, AND IMMUNITY 4, 10%117 (1%)) Effects of Repeated Stress on T Cell Numbers and Function in Rats OLCAY A. BATUMAN, **l DANIEL SAJEWSKI,* JOHN E. OTTENWELLER,~~ DAVID L. PITMAN,? AND BENJAMIN H. NATELsoNt’$ Medicine Service, *Division of Hematology and fNeurology Service, VA Medical Center, East Orange, New Jersey 07019 and fDepartment of Neurosciences, New Jersey Medical School, Newark, New Jersey 07013 Although stress has been reported to affect various functions of the immune system, the mechanism that mediate these effects remain unclear. Thus we examined the effects that 1,7, and 14 days of stress could have on various aspects of immune and endocrine function in rats. Rats subjected to repeated stress (7 and 14 days) showed significant decreases in the total number of mononuclear cells, particularly suppressor/cytotoxic (CDS) T cells, in the spleen and blood. The mitogenic responses of T cells to phytohe- magglutinin (PHA) and concanavalin-A (Con A) were also significantly diminished at these times, as well as after acute (1 day) stress in the case of PHA stimulation. The mechanisms of this impaired T cell mitogenesis were explored by assessing the effects of stress on T cell interleukin 2 (IL-2) production and T cell responsiveness to IL-2. T cells from repeatedly stressed rat showed a decreased production of IL-2 in response to PHA, although their proliferative response to exogenous IL-2 was normal. Repeated stress also decreased body weight and spleen weight, increased adrenal weight, and decreased plasma levels of triiodothyronine and testosterone. These results suggest that lower levels of IL-2 production during stress could be one reason for the decreased mitogen responsiveness of T cells, often seen with stress. This is important because defective IL-2 production could also lead to significant impairment of immunoregulatory T cell generation and thus a predisposition to malignancy or autoimmune disease that some have associated with stress. o 1990 Academic PWSS, IK. INTRODUCTION Recent research has shown that psycholo ical stress can have inhibitory effects on the immune system. Acute or repeate \ stress in animal models as well as humans has been associated with decrease proliferative responses to T or B cell mitogens (Joasco & McKenzie, 1976; Bartr p e? al., 1977; Monjan & Collector, 1977; Reite, Harbeck, & Hoffman, 1981; Kell r, Weiss, Schleifer, Miller, & Stein, 1981), decreased T cell responsiveness in mi I ed lymphocyte reactions (Calabrese, Kling, & Gold, 1987), impaired natural killer (NK) cell activity (Steplewski dz Vogel, 1986), and lymphopenia with altered helper (CD4)/suppressor (CD8) T cell ratios in peripheral blood (Ader, 1981). To date, the mechanisms that mediate these changes in lymphocyte function have not been elucidated. In view of the fact that T cell mitogenesis depends upon the production of and response to IL-2, we have examined the possibility that IL-2 has a role in the immunological ab- ’ Send correspondence and reprint requests to: Olcay A. Batuman, M.D., Cardeza Foundation for Hematologic Research, Jefferson Medical College, 1015 Walnut Street, Philadelphia, PA 19107. 105 0889-1591/90 $3.00 Copyright 8 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.