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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088989-05
Application #
8197357
Study Section
Special Emphasis Panel (ZRG1-AARR-C (04))
Program Officer
Peavy, Hannah H
Project Start
2007-12-06
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$366,250
Indirect Cost
$116,250
Name
University of Kentucky
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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-ýý. J Immunol 191:1792-9
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