Pneumocystis pneumonia is an AIDS-defining illness that has continued to cause significant morbidity and mortality among HIV-infected patients with compromised CD4 T cells. Susceptibility to Pneumocystis (PC) infection is largely due to reduced CD4 T cell number or function, however, B cells are also critical for host defense against PC. Using murine models, we have found that B-T cell interactions through costimulatory molecules such as MHC class II and CD40 on B cells have profound effects on T cell function. In the absence of B cells, CD4 T cells are not primed appropriately and fail to expand when transferred into PC-infected mice lacking T or B cells (severe combined immunodeficient, SCID mice). We hypothesize that cognate interactions in draining lymph nodes between T and B cells within the first week after PC infection provides signals for T cell expansion and CD4 T cell memory generation.
Our specific aims for addressing this hypothesis are as follows: 1. To determine whether cognate or costimulatory interactions between B and T cells are required for proliferation and survival of CD4 T cells. 2. To determine whether cytokine production by B cells drives T cell survival, expansion, or memory cell generation. We will utilize established murine models of PC infection to address these three aims. These models include generation of mixed chimeric mice whose B cells are deficient in costimulatory molecules or cytokines, adoptive transfer models in which T cells are primed in the presence or absence of B cells and then transferred to SCID hosts, inducible depletion of dendritic cells using transgenic mice, and depletion of B cells using a drug combination relevant to HIV disease. In addition to determining what molecules are critically involved in T-B cell interactions, we will also perform kinetics experiments to determine when during the immune response these critical interactions take place. In addition to reduced CD4 T cell numbers, HIV-infected patients have abnormal B cell function that is related to viral load. Understanding how T and B cells must interact for efficient control of opportunistic infections is critically important for devising strategies to prevent these often times fatal opportunistic infections.
|Opata, Michael M; Hollifield, Melissa L; Lund, Frances E et al. (2015) B Lymphocytes Are Required during the Early Priming of CD4+ T Cells for Clearance of Pneumocystis Infection in Mice. J Immunol 195:611-20|
|Opata, Michael M; Ye, Zhan; Hollifield, Melissa et al. (2013) B cell production of tumor necrosis factor in response to Pneumocystis murina infection in mice. Infect Immun 81:4252-60|
|Breslow-Deckman, Jessica M; Mattingly, Cynthia M; Birket, Susan E et al. (2013) Linezolid decreases susceptibility to secondary bacterial pneumonia postinfluenza infection in mice through its effects on IFN-Î³. J Immunol 191:1792-9|
|Kurkjian, Cathryn; Hollifield, Melissa; Lines, J Louise et al. (2012) Alveolar macrophages in neonatal mice are inherently unresponsive to Pneumocystis murina infection. Infect Immun 80:2835-46|