Short-term corticosterone treatment decreases the early CD8+ T cell response to simian virus 40 tumor antigen but has no impact on the late CD8+ T cell response.

CD8+ T cells (T(CD8)) help control tumor growth in vivo through recognition of distinct tumor antigens and cytolysis of tumor cells. The T(CD8) immune response in C57BL/6 mice to the Simian Virus 40 oncoprotein, large tumor antigen (Tag), targets multiple epitopes and is well-characterized. Epitope IV, an H-2K(b)-restricted epitope, is immunodominant while epitope I, an H-2D(b)-restricted epitope is subdominant. GCs alter many aspects of T cell function. Indeed, the current studies demonstrate that exposure of mice to the immunosuppressive GC, corticosterone (CORT), over the entire course of the primary immune response limits activation of endogenous Tag-specific T(CD8). Even short-term CORT treatment from day -1 to day +2 post-immunization significantly reduced splenic size and the absolute number of Tag-specific T(CD8) on day 6 post-immunization. In vivo killing activity was also reduced. However, by day 10 post-immunization, the peak of the immune response, the absolute number of Tag-specific T(CD8) and their in vivo killing of epitope I or epitope IV-expressing target cells had recovered in CORT treated mice. Adoptive transfer of transgenic T cells post-CORT removal demonstrated that CORT decreased the ability of the endogenous antigen-presenting cells to induce proliferation of the exogenous transgenic T cells. Combined, these studies have implications about the timing of clinical steroid treatment relative to immunization or adoptive transfer for cancer immunotherapy.

Elevated maternal corticosterone during lactation hinders the neonatal adaptive immune response to herpes simplex virus (HSV) infection.

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.

Rapid accumulation of adoptively transferred CD8+ T cells at the tumor site is associated with long-term control of SV40 T antigen-induced tumors.

We previously established a model to study CD8(+) T cell (T(CD8))-based adoptive immunotherapy of cancer using line SV11 mice that develop choroid plexus tumors in the brain due to transgenic expression of Simian Virus 40 large T antigen (Tag). These mice are tolerant to the three dominant T(CD8)-recognized Tag epitopes I, II/III and IV. However, adoptive transfer of spleen cells from naïve C57BL/6 (B6) mice prolongs SV11 survival following T(CD8) priming against the endogenous Tag epitope IV. In addition, survival of SV11 mice is dramatically increased following transfer of lymphocytes from Tag-immune B6 mice. In the current study, we compared the kinetics and magnitude of Tag-specific T(CD8) accumulation at the tumor site following adoptive transfer with a high dose of either Tag-immune or naïve donor cells or decreasing doses of Tag-immune lymphocytes. Following adoptive transfer of Tag-immune cells, epitope I- and IV-specific T(CD8) accumulated to high levels in the brain of SV11 mice, peaking at 5-7 days, while epitope IV-specific T(CD8 )derived from naïve donors required three weeks to achieve peak levels. A similar delay in the peak of epitope IV-specific T(CD8) accumulation was observed when tenfold fewer Tag-immune donor cells were administered, reducing control of tumor progression. These results suggest that efficient and prolonged control of established autochthonous tumors is associated with high-level early accumulation of adoptively transferred T cells. We also provide evidence that although multiple specificities are represented in the Tag immune donor lymphocytes, epitope IV-specific donor T(CD8) play a predominant role in control of tumor growth.

Impact of maternal stress on the transmammary transfer and protective capacity of herpes simplex virus-specific immunity.

In adults, psychological stress regulates immune responsiveness in part via the increased levels of corticosterone that are produced as a result of hypothalamic-pituitary-adrenal (HPA) axis activation. However, there is a lack of knowledge as to the role such regulation may play in the neonate. Neonates are severely compromised in their ability to generate an immune response to pathogens encountered after birth and therefore rely heavily on maternally derived antibody acquired postnatally through the milk. This passive transfer of antibody is critical for protection of the neonate from severe herpes simplex virus (HSV) infection and mortality. Using a well-established postnatal restraint/light stress model, we determined whether maternal stress and the associated increases in corticosterone would affect the transmammary transfer of antibody and subsequent neonate susceptibility to HSV-associated mortality. Serum corticosterone levels were markedly increased in lactating mice subjected to the restraint/light stress, and increased levels of corticosterone were transferred through the milk of these stressed mothers to their neonates. Despite these increases in corticosterone, the transmammary transfer and accumulation of total and HSV-specific IgG in neonate serum remained intact. This milk-derived, HSV-specific antibody alone protected the neonate from systemic viral spread. Interestingly, postnatal maternal stress significantly increased neonate survival after HSV-2 infection despite no apparent alteration in viral spread. These studies demonstrate that although the transmammary transfer of antibody is unaffected by maternal stress, stress may be enhancing components of antiviral immunity that are effective in protecting neonates from HSV-associated mortality.

Postpartum maternal corticosterone decreases maternal and neonatal antibody levels and increases the susceptibility of newborn mice to herpes simplex virus-associated mortality.

The effects of corticosterone on the transmammary transfer of herpes simplex virus (HSV)-specific antibody and the ability of the neonate to survive HSV-2 infection were assessed. Increased postpartum maternal corticosterone reduced the levels of total and HSV-specific IgG in the serum and milk of mothers. Neonates nursed by these mothers received increased levels of corticosterone and decreased levels of total and HSV-specific IgG. Accordingly, these neonates were more susceptible to HSV-2-associated mortality; however, survival was restored through passive immunization with HSV-specific antibody. These studies demonstrate that postpartum elevations in corticosterone compromise a mother's ability to provide protective antibody to their offspring.

Prenatal transfer of low amounts of herpes simplex virus (HSV)-specific antibody protects newborn mice against HSV infection during acute maternal stress.

Given their immunocompromised status, neonates rely heavily upon maternally derived, herpes simplex virus (HSV)-specific antibody for resistance to HSV infection. Interestingly, previous studies have documented a decreased transfer of maternal IgG antibody and immunocompetence of the offspring following perinatal exposure to stress-induced corticosterone. However, we recently demonstrated that the transplacental transfer of relatively high amounts of HSV-specific antibody is resilient to acute maternal stress and protects neonatal mice against HSV-2-associated mortality. Our current studies demonstrate that transplacentally acquired, HSV-specific antibody declines rapidly in neonate serum such that by day 7 postnatal only 10% of this antibody remains. Prenatal stress does not affect the overall kinetics with which the HSV-specific antibody declines. Surprisingly, this relatively low level of antibody is still sufficient to protect 7-day-old mice against HSV-associated mortality. To extend these studies, we utilized an immunization strategy that elicits low levels of HSV-specific antibody in maternal serum. We demonstrated that despite a stress-induced increase in corticosterone, the prenatal transfer and protective capacity of low amounts of HSV-specific antibody remains intact during acute maternal stress.

Transplacental transfer and subsequent neonate utilization of herpes simplex virus-specific immunity are resilient to acute maternal stress.

Neonates are severely compromised in the ability to generate an immune response to pathogens and thus rely heavily on maternally derived immunity that is acquired by transplacental and transmammary means. The passive transfer of maternal herpes simplex virus (HSV)-specific antibody is critical in determining the outcome of neonatal HSV infection. In adults, psychological stress alters immune responsiveness via the increased level of corticosterone that is produced as a result of hypothalamic-pituitary-adrenal axis activation. Although the behavioral and neuroendocrine effects of pre- and postnatal stress-induced increases in corticosterone are well documented, the effects of maternal stress on the efficacy of prenatally transferred and neonatally developed viral immunity has yet to be addressed. By using a well-established prenatal restraint-and-light stress mouse model, we investigated the effects of increased maternal corticosterone on the passive transfer of total and HSV-specific immunoglobulin G (IgG) antibody and subsequent neonatal susceptibility to HSV infection. Serum corticosterone levels in pregnant mice were significantly increased in response to restraint-and-light stress, and fetuses derived from these stressed mice had significantly elevated levels of corticosterone. Despite the increases in corticosterone, the passive transfer of total and HSV-specific IgG antibody persisted and, in turn, protected the neonate from systemic viral spread. Therefore, prenatal stress did not increase the susceptibility of neonates to HSV type 2-associated mortality. These findings demonstrate the resiliency of the passive transfer of protective HSV-specific immunity under conditions of acute psychological stress.