Protein energy malnutrition impairs homeostatic proliferation of memory CD8 T cells.

Nutrition is a critical but poorly understood determinant of immunity. There is abundant epidemiological evidence linking protein malnutrition to impaired vaccine efficacy and increased susceptibility to infections; yet, the role of dietary protein in immune memory homeostasis remains poorly understood. In this study, we show that protein-energy malnutrition induced in mice by low-protein (LP) feeding has a detrimental impact on CD8 memory. Relative to adequate protein (AP)-fed controls, LP feeding in lymphocytic choriomeningitis virus (LCMV)-immune mice resulted in a 2-fold decrease in LCMV-specific CD8 memory T cells. Adoptive transfer of memory cells, labeled with a division tracking dye, from AP mice into naive LP or AP mice demonstrated that protein-energy malnutrition caused profound defects in homeostatic proliferation. Remarkably, this defect occurred despite the lymphopenic environment in LP hosts. Whereas Ag-specific memory cells in LP and AP hosts were phenotypically similar, memory cells in LP hosts were markedly less responsive to polyinosinic-polycytidylic acid-induced acute proliferative signals. Furthermore, upon recall, memory cells in LP hosts displayed reduced proliferation and protection from challenge with LCMV-clone 13, resulting in impaired viral clearance in the liver. The findings show a metabolic requirement of dietary protein in sustaining functional CD8 memory and suggest that interventions to optimize dietary protein intake may improve vaccine efficacy in malnourished individuals.

Diminished primary CD8 T cell response to viral infection during protein energy malnutrition in mice is due to changes in microenvironment and low numbers of viral-specific CD8 T cell precursors.

Protein energy malnutrition (PEM) increases the incidence and severity of infection, causing morbidity and mortality in malnourished populations. Viral-specific cells are an important component of protective immunity. We hypothesized that reduction in the expansion of viral-specific cells and the microenvironment of the PEM host leads to increased incidence and severity of infections. We tested this hypothesis using a mouse model of lymphocytic choriomeningitis virus (LCMV) infection and an adoptive transfer system using P14 transgenic mice cells bearing T cell receptors specific for the D(b)-restricted LCMV glycoprotein 33-41 epitope. We transferred equal numbers of P14 cells from mice fed either an adequate, 18% protein or low, 0.6% protein diet into C57BL/6 mice that had been fed adequate-protein (AP) or low-protein (LP) diets for 2 wk, infected them with LCMV, and followed them 1 wk postinfection. During PEM, the expansion of primary viral-specific CD8 T cells diminished; in LP diet-fed mice, it was only 2-3% of that in the AP diet-fed mice. Furthermore, the diminished primary CD8 T cell response during PEM may in part have been due to low numbers of viral-specific CD8 T cells and an altered microenvironment.

Suppression of viral specific primary T-cell response following intense physical exercise in young but not old mice.

Intense exercise to exhaustion leads to increased susceptibility and severity of infections. T cells play an essential role in control of viral infections. Whereas immune suppression is considered as a likely mechanism for exhaustive exercise-induced susceptibility to infection, we know little about viral-specific T-cell response following exhaustive exercise in young or old mice. In this study, one group of female young (10-12 wk) and old (22-24 mo) C57BL/6 mice was exposed to a single bout of intense exercise to exhaustion and immediately infected with lymphocytic choriomeningitis virus (LCMV). Eight days later, at the peak of expansion phase of T-cell response, we used tetramers of MHC class I molecules containing viral peptides to directly visualize antigen-specific CD8 T cells and a sensitive functional assay measuring interferon-gamma production at the single-cell level to quantitate the CD8 and CD4 T-cell response. To evaluate the impact of intense exercise during both the initiation and evolution of the expansion phase of the T-cell response, a second group of young and old mice continued their daily bouts of intense exercise to exhaustion over the next 8 days. Our data show that, in young mice, LCMV infection following exhaustive exercise leads to suppression of LCMV-specific CD8 and CD4 T-cell responses, and this suppression effect occurs at the initiation of the expansion phase of viral-specific T cells. However, in old mice, unlike young mice, exhaustive exercise does not cause suppression of LCMV-specific T-cell responses.

Effects of an exercise intervention on immunologic parameters in frail elderly nursing home residents.

BACKGROUND: Aging is associated with decline in both cell-mediated and humoral immunity and may contribute to increased incidence and severity of infections in frail elderly. Exercise, depending on intensity, has significant effects on the immune system. We conducted a randomized, controlled clinical trial of a 32-week functionally oriented exercise program in frail elderly living in nursing homes and determined whether the exercise intervention was associated with a change in immune parameters in this frail elderly nursing home population. METHODS: Nursing home residents were randomly assigned to an intervention (n = 94) and control group (n = 96). The intervention consisted of a functionally oriented endurance and resistance exercise training that was provided every 2 hours from 8:00 AM to 4:00 PM for 5 days a week for 8 months. Lymphocyte subpopulations, including activation markers (CD28, CD25, HLA-DR), in vitro proliferation, and soluble products of cytokine activity (neopterin and sTNF-RII) in serum were measured by taking blood samples at baseline and after 8 weeks and 32 weeks of the intervention. RESULTS: Exercise training did not induce changes in lymphocyte subpopulations, activation markers (CD28, CD25, HLA-DR), in vitro proliferation, and soluble products of cytokine activity (neopterin and sTNF-RII) in serum. CONCLUSIONS: A 32-week exercise intervention did not bring about beneficial or detrimental effects on immune parameters in the frail elderly nursing home population and may explain why the intervention was not associated with a change in the incidence of infections in the intervention group compared with the control group.

Effect of duration of a moderate exercise program on primary and secondary immune responses in mice.

BACKGROUND AND PURPOSE: Moderate exercise conducted over a 4- to 8-week period enhances secondary antibody response and is mediated, in part, by endogenous opioids. Because changes in circulating levels of endogenous opioids occur after each exercise session, the researchers in this study tested the hypothesis that a shorter exercise program of 2 weeks may be sufficient to enhance secondary antibody response. Another purpose of this study was to examine the effects of a moderate exercise program completed prior to the primary immunization on the secondary antibody response in mice. SUBJECTS AND METHODS: Young (8- to 10-week-old), syngeneic, female C57BL/6 mice were randomly assigned to exercise (2 or 8 weeks) and sedentary intervention protocols. Mice were immunized against human serum albumin (HSA), and serum anti-HSA antibody levels were measured (in micrograms per milliliter) using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The secondary antibody response was comparable in mice exercising for 2 or 8 weeks and was enhanced over sedentary controls. DISCUSSION AND CONCLUSION: A moderate exercise program of 2 weeks may be sufficient to improve secondary antibody production and may be a useful strategy to enhance antibody response to vaccinations in humans. Furthermore, an exercise program that includes exercise prior to the primary immunization in addition to exercise following primary immunization may not provide additional enhancement of secondary antibody response.

Defective generation but normal maintenance of memory T cells in old mice.

The ability to maintain memory after encounter with antigen is one of the central features of the immune system. Immune memory generated during young age can be maintained well into old age. However, we know little about maintenance of immune memory generated during old age. In this study, we compared generation and maintenance of memory CD8 T cells in young (2-3-month-old) and aged (22-24-month-old) mice following acute lymphocytic choriomeningitis virus infection. We found that young mice made a more vigorous primary T cell response and generated higher levels of memory cells than old mice. However, once generated, memory CD8 T cells were maintained at stable levels in both young and old mice for more than 5 months. Interestingly, the generation of a secondary effector response in vivo was again slightly compromised in the old mice. Taken together, these results show that generation of T cell responses is compromised in old age, but maintenance of the pool of memory T cells is not affected by the aging process.