There has been a lot of attention given recently to the role of gut CD4 T cell depletion in HIV pathogenesis. Surprisingly, very little is known about which antigens are targeted by gut CD4 T cells; at least one study has reported evidence of memory CD4 T cell responses to candida albicans (the fungus that causes thrush) but an absence of the typical memory responses against opportunistic pathogens (also called “recall responses”) found in the blood. More recently, gut HIV-specific CD4 T cell responses have been detected in some elite controllers and in HIV-infected individuals showing robust CD4 T cell recovery in the gut on antiretroviral therapy (this latter data was presented at CROI by Satya Dandekar, see the second talk in this webcast). Studies in mice have suggested that there are likely be CD4 T cell responses to commensal bacteria in the gut, but there is little research addressing this question in humans. In a new paper in press at Clinical Immunology, Rawleigh Howe and colleagues from Cara Wilson’s group at the University of Colorado describe their initial efforts to fill this knowledge gap.
Using flow cytometric techniques, the researchers were able to detect the presence of CD4 T cells making interferon gamma in response to stimulation with several gut commensal bacteria species (Enterobacter, E. coli, Enterococcus species) as well as to the pathogen, Salmonella typhimurium. CD4 T cells making IL-17 – Th17 cells – were also detected but at a much lower frequency. Bacteria-specific CD4 T cell responses could also be detected in the blood but at significantly lower levels; the difference in magnitude between gut and blood ranged from 8.5 to 19.5 fold. When responses to all four bacterial antigens were summed, the median frequency of interferon gamma-producing CD4 T cells was 0.24% in the gut compared to 0.02% in blood.
The researchers suggest that the CD4 T cell responses revealed in this study play a role in containing bacteria in the gut under normal conditions. Such a role would be consistent with recent studies indicating that T cell depletion can lead to systemic dissemination of gut bacteria (microbial translocation). Another implication of the data is that people with HIV infection may have altered CD4 T cell reactivity to commensal bacteria, and Cara Wilson’s group is addressing this possibility in ongoing studies.
Article in Press
Rawleigh Howe a, Stephanie Dillon a, Lisa Rogers a, Martin McCarter b, Caleb Kelly a, Ricardo Gonzalez b, Nancy Madinger a and Cara C. Wilson a.
a Department of Medicine, University of Colorado Denver, Denver, Colorado 80045, USA
b Department of Surgery, University of Colorado Denver, Denver, Colorado 80045, USA
Received 23 September 2008; accepted 10 December 2008. Available online 27 January 2009.
Reactivity of lamina propria (LP) T cells to commensal bacteria has been demonstrated in animal models of inflammatory bowel disease (IBD) and in humans with IBD, but few studies have evaluated the function of such cells in normal individuals. LP mononuclear cells (LPMC) were disaggregated from healthy human intestinal tissue and cultured with heat-killed commensal and pathogenic bacteria. CD3+CD4+ IFN-γ-producing (Th1) cells reactive to commensal bacteria were demonstrated at frequencies ranging from 0.05 to 2.28% in LPMC. Bacteria-specific Th1 responses were inhibited by anti-HLA-DR antibodies and chloroquine exposure, were enriched in LP relative to peripheral blood, and expressed effector memory cell markers. Bacteria-specific CD4+ T cell proliferation in vitro was dependent on the presence of LP dendritic cells (DCs), which produced pro-inflammatory cytokines upon bacterial exposure. These results suggest that bacteria-reactive DCs and CD4+ T cells in normal LP have substantial pro-inflammatory potential that is revealed upon disaggregation in vitro.