T-cell phenotypic and functional changes associated with social subordination and gene polymorphisms in the serotonin reuptake transporter in female rhesus monkeys

Abstract

Increased vulnerability to psychosocial stressors likely predisposes individuals to decreased immune function and inability to control pathogens. While many factors influence the susceptibility to psychosocial stress, genetic polymorphisms may modify individual reactivity to environmental stressors. The present study evaluated how immune function was altered by the interaction of in polymorphisms in the gene that encodes the serotonin reuptake transporter (5HTT) and the psychosocial stress imposed by social subordination in adult female rhesus monkeys. Subjects were dominant and subordinate females that carried both alleles of the long promoter variant (l/l) of the 5HTT gene, and dominant and subordinate that had at least one allele for the short promoter length variant (l/s or s/s, s-variant). Plasma cortisol was higher in subordinate females in response to a social separation paradigm, confirming their increased reactivity to psychosocial stressors. Subordinate females exhibited increased T-cell activation and proliferation regardless of genotype. Despite these higher levels of T-cell proliferation and activation, subordinate females showed significantly lower frequency of T-cells. This latter finding may be due to an increased susceptibility to cell death, as indicated by higher levels of annexin-V+ CD4+ and CD8+ T-cells in s-variant subordinate compared to dominant females. These findings indicate that subordinate rhesus monkeys with the s-variant 5HTT genotype exhibit decreased T-cell numbers perhaps compromising their ability to mount an immune response to pathogens. These data underscore the importance for considering gene polymorphisms that influence emotional reactivity to better understand susceptibility to disease.

Immunovirological Analyses of Chronically Simian Immunodeficiency Virus SIVmnd-1- and SIVmnd-2-Infected Mandrills (Mandrillus sphinx)

“…This finding suggests that the prevailing level of CD4 ϩ T cell depletion and/or proliferation may have a different biological significance in natural hosts than in HIV-infected individuals. In this view, the level of CD4 ϩ T cell proliferation would mainly reflect, in humans, the level of immune activation in response to viral replication (20), while in natural SIV hosts, this parameter may reflect homeostatic mechanisms aimed at compensating for virus-induced cell loss (34). This interpretation is also supported by previous studies reporting that, in SMs and AGMs, the suppression of viral replication with antiretroviral therapy is not immediately followed by a decline in the fraction of Ki-67 ϩ T cells (18,44), as reported in HIVinfected patients (20).…”

Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys

“…Importantly, the maximal proliferation level Relationship between CD4þ T cell number and proliferation level (by Ki67 expression): experimental data are shown from pathogenic infection of (a) rhesus macaques (RMs) or (b) HIV infection, as well as natural host infection of (c) sooty mangabeys (SMs) or (d) mandrills. The experimental data for RMs, humans and SMs are obtained from previously published studies (Paiardini et al 2005(Paiardini et al , 2009bSumpter et al 2007;Brenchley et al 2008;Dunham et al 2008;Engram et al 2009) and for mandrills from unpublished results. All of the species except mandrills show a significant negative correlation between CD4þ T cell count and the proportion of cells Ki67þ (Spearman correlation).…”

“…Four RMs were inoculated with SIV mac239 (Engram et al 2009), while 31 of them were uninfected (Paiardini et al 2009b). Of all the 35 RMs, we had single data points from 30 RMs and longitudinal data for five RMs.…”

A Five-Year Longitudinal Analysis of Sooty Mangabeys Naturally Infected with Simian Immunodeficiency Virus Reveals a Slow but Progressive Decline in CD4+T-Cell Count Whose Magnitude Is Not Predicted by Viral Load or Immune Activation

“…Since natural SIV infections are characterized by chronically high levels of virus replication occurring primarily in short-lived CD4 ϩ T cells, it does not appear that natural SIV hosts remain healthy due to stronger or more effective adaptive immune responses to the virus or that the virus is intrinsically less cytopathic in these animals (9,41,51). In recent studies, more emphasis has been placed on other factors, such as the absence of chronic immune activation, more vigorous CD4 ϩ T-cell regeneration, and lower levels of CCR5 expression on CD4 ϩ T cells (40,43,52,56). Elucidating the mechanisms responsible for the AIDS resistance of natural SIV hosts may provide important insight into the mechanisms of AIDS pathogenesis in HIV-infected humans.…”