Selective impairment in dendritic cell function and altered antigen‐specific CD8⁺ T‐cell responses in diet‐induced obese mice infected with influenza virus

Abstract

Summary There is a clear link between obesity and metabolic disorders; however, little is known about the effect of obesity on immune function, particularly during an infection. We have previously reported that diet‐induced obese mice are more susceptible to morbidity and mortality during influenza infection than lean mice. Obese mice displayed aberrant innate immune responses characterized by minimal induction of interferon (IFN)‐α/β, delayed expression of pro‐inflammatory cytokines and chemokines, and impaired natural killer cell cytotoxicity. To further examine the abnormal immune response of diet‐induced obese mice, we analysed the cellularity of their lungs during influenza virus infection. We found delayed mononuclear cell entry with a marked decrease in dendritic cells (DCs) throughout the infection. Given the critical role of the DC in activating the cell‐mediated immune response, we also analysed the functional capacity of DCs from obese mice. We found that, while obesity did not interfere with antigen uptake and migration, it did impair DC antigen presentation. This was probably attributable to an altered cytokine milieu, as interleukin (IL)‐2, IL‐12, and IL‐6 were differentially regulated in the obese mice. Overall, this did not impact the total number of virus‐specific CD8+ T cells that were elicited, but did affect the number and frequency of CD3+ and CD8+ T cells in the lung. Thus, obesity interferes with cellular responses during influenza infection, leading to alterations in the T‐cell population that ultimately may be detrimental to the host.

Changes in human dendritic cell number and function in severe obesity may contribute to increased susceptibility to viral infection

“…22 This study reports similar findings in severe human obesity, demonstrating high levels of the immunosuppressive cytokine IL-10 in response to LPS stimulation of obese DCs, and increased phosphorylation of the immunosuppressive transcription factor CREB. Furthermore, we show a significant increase in the production of the Th2 cytokine IL-4 from T cells co-cultured with obese DCs.…”

Impact of obesity on mortality in hospitalized patients with pneumonia due to 2009 H1N1 Influenza A virus versus other etiologies.

“…[4][5][6][7] Animal studies indicate that the production of interferon is significantly decreased in diet-induced, obese mice when compared to lean, control animals. 15,16 Decreased production of interferon in obese patients may explain the poor outcomes associated with pneumonia due to 2009 H1N1 influenza A virus.…”

Obesity and risk of pneumonia in patients with influenza

“…The latter possibility has been examined in several studies in rodents. SMITH et al [5] have demonstrated that diet-induced obese mice were more susceptible to morbidity and mortality during influenza infection than lean mice, namely due to altered innate immune responses characterised by minimal induction of interferon-a/b, delayed expression of pro-inflammatory cytokines and chemokines, impaired natural killer cytotoxicity and impaired dendritic cell presentation. Thus, the function of influenza-specific memory T-cells is significantly reduced and ineffective in obese mice.…”