The Binding Site for TRAF2 and TRAF3 but Not for TRAF6 Is Essential for CD40-Mediated Immunoglobulin Class Switching

AbstractTo define the role of TRAF proteins in CD40-dependent isotype switching in B cells, we introduced wild-type (WT) and mutant CD40 transgenes that lacked the binding motifs for TRAF6 (CD40ΔTRAF6), TRAF2 and TRAF3 (CD40ΔTRAF2/3), or both (CD40ΔTRAFs) into B cells of CD40−/− mice. The in vivo isotype switch defect in CD40−/− mice was fully corrected by WT and CD40ΔTRAF6, partially by CD40ΔTRAF2/3, and not at all by CD40ΔTRAFs transgenes. CD40-mediated isotype switching, proliferation, and activation of p38, JNK, and NFκB in B cells were normal in WT and CD40ΔTRAF6 mice, severely impaired in CD40ΔTRAF2/3, and absent in CD40ΔTRAFs mice. These results suggest that binding to TRAF2 and/or TRAF3 but not TRAF6 is essential for CD40 isotype switching and activation in B cells

TB-IRIS, T-cell activation, and remodeling of the T-cell compartment in highly immunosuppressed HIV-infected patients with TB

The authors are indebted to Wallis Annenberg whose generosity made this study possible, and to John Moores for his generous gift. We are grateful to Francoise Barré-Sinoussi for her help, advice, and support over the years. We thank Eric Nerrienet, Claire Rekacewicz, Daniel Scott, Gianfranco Pancino, Jean-Louis Sarthou, and Charles Mayaud for helpful discussions and advice as we began the study, and Jean-Louis Sarthou for his long time support of the Harvard team’s collaboration with the Institut Pasteur du Cambodge. We thank the CAMELIA study team, including the site nurses, doctors, and health workers, and Vincent Deubel and the staff at the Institut Pasteur du Cambodge. We thank Larry Fox, Rod Hoff, Jane Bupp, and Brigitte Bazin for their support and helpful discussions from the beginning of CAMELIA onward and the staff of the Cambodian Health Committee, especially Sam Sophan, for his contributions to and support of the work. We thank Leslie Kalish of Children’s Hospital Boston and the Harvard Catalyst Biostatistical Consulting program (NIH UL1 TR001102) for expert statistical advice and help as we started the analysis. We also thank Jerry Sadoff for his early support and Judy Lieberman for helpful comments on the manuscript. Finally, we are deeply indebted to the patients who took part in this study, who generously offered their participation to help the scientific community find solutions to AIDS and TBInternational audienceOBJECTIVE: To investigate the impact of tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) upon immunological recovery and the T-cell compartment after initiation of TB and antiretroviral therapy (ART).DESIGN AND METHODS: We prospectively evaluated T-cell immunophenotypes by flow cytometry and cytokines by Luminex assays in a subset (n = 154) of highly immunosuppressed HIV-infected patients with TB from the Cambodian Early versus Late Introduction of Antiretrovirals randomized clinical trial. We compared findings from patients who developed TB-IRIS with findings from patients who did not develop TB-IRIS. Data were evaluated with mixed-effect linear regression, Kaplan-Meier estimates, and Wilcoxon rank-sum tests, and q-values were calculated to control for multiple comparisons.RESULTS: Development of TB-IRIS was associated with significantly greater pre-ART frequencies of HLA-DRCD45ROCD4, CCR5CD4, OX40CD4, and Fas effector memory CD8 T cells, and significantly elevated levels of plasma interleukin (IL)-6, IL-1β, IL-8, and IL-10, and viral load. Post-ART initiation, effector memory CD4 and Fas effector memory CD4 T-cell frequencies significantly expanded, and central memory CD4 T-cell frequencies significantly contracted in patients who experienced TB-IRIS. By week 34 post-TB treatment initiation, effector memory/central memory CD4 T-cell ratios were markedly higher in TB-IRIS versus non-TB-IRIS patients.CONCLUSIONS: A distinct pattern of pre-ART T-cell and cytokine markers appear to poise the immune response of certain patients to develop TB-IRIS. Experience of TB-IRIS is then associated with long-term remodeling of the CD4 T-cell memory compartment towards an effector memory-dominated phenotype. We speculate that these pre and post-ART TB-IRIS-associated immune parameters may contribute to superior immune control of TB/HIV co-infection and better clinical outcome