The neonate's immune system is relatively immature. For short-term protection against pathogens the neonate is reliant primarily on maternally derived antibodies delivered via the mother's milk. However, neonates soon acquire the ability to generate adaptive immune responses for long-term protection. Products of the nervous and endocrine systems that are elicited by psychological stress are known to modulate a variety of immune responses. Additionally, psychological stressors are well recognized for their ability to increase corticosterone levels. The studies described herein examined the effects of increases in maternally derived corticosterone on the neonatal cell-mediated immune response to, and pathogenicity of, herpes simplex virus (HSV) infection. Water containing corticosterone was made available to nursing mothers for a period of 6 consecutive days beginning on either the day of or 6 days post-delivery. At 12 days of age, neonates were infected with HSV-1 in the rear footpads. These neonates exhibited a decrease in the proliferative ability of splenic-derived cells due to the reduction of IL-2 production and IL-2 receptor alpha subunit (IL-2R alpha) expression by these cells. These neonates also exhibited a decrease in the number and function of popliteal lymph node-resident HSV-1 gB(498-505) peptide-specific CD8(+) T cells as measured by tetramer analysis, CTL lytic activity, expression of CD107a, cytokine production, and proliferation. Additionally, these HSV-infected neonates exhibited increased morbidity and mortality. Together, these studies indicate that exposure of neonates to maternally derived corticosterone via the milk hinders their ability to generate an adaptive cell-mediated immune response to a viral infection and illustrate the potential importance of maternal stress in neonatal resistance to infectious pathogens.