T cell memory
There is a significant need to improve vaccine-induced immunity against infectious diseases. Memory T cells are induced by vaccines and after infection, and they play a key role in long-term immune protection. We study how virus-specific T cell responses are initiated after infection and how T cell memory forms. We use in vivo models of live virus infection to examine T cell and B cell responses following acute or chronic virus infection. Much of our research focuses on understanding how interferons and costimulatory molecules influence the differentiation of effector and memory CD4+ and CD8+ T cell responses. The overall goal is to better understand the underlying mechanisms that stimulate long-term immunity so that this information can be used to better design protective vaccines. The two main areas of research in the lab are:
• To define the molecular interactions that induce T cell responses and lead to memory.
Our investigations show that type-1 (IFNαβ) and type-2 (IFNγ) interferons signal directly into antiviral T cells to profoundly enhance the formation of antiviral memory T cells. We are currently examining the molecular and cellular mechanisms by which interferons propel T cell responses and exploring methods to deliver these signals to enhance vaccine-induced memory. We are also studying the effects of other inflammatory stimuli in the differentiation of memory T cells. Our long-range goals here are to identify specific molecular pathways that can be manipulated to enhance vaccine-induced T cell memory.
• To examine the role of B cells in CD4 T cell memory.
CD4+ T cells deliver signals to B cells, which enables B cells to differentiate into memory B cells and plasma cells; this interaction is crucial for driving humoral immunity against many pathogens. We have discovered that B cells are also needed to form protective levels of T cell memory. We are currently studying how B cells contribute to T cell memory by characterizing when B cells exert their effects, determining whether B cells deliver essential survival signals to memory cells, and examining the role of immune-complexes in the formation of CD4+ T cell memory.
Whitmire JK (2011). Induction and function of virus-specific CD4+ T cell responses. Virology. 411(2):216-28.
Botten J, Whitton JL, Barrowman P, Sidney J, Whitmire JK, Alexander J, Kotturi MF, Sette A, Buchmeier MJ (2010). A multivalent vaccination strategy for the prevention of Old World arenavirus infection in humans. J Virol. 84(19):9947-56.
Whitmire, J.K. ♣, M.S. Asano, S.M. Kaech, S. Sarkar, L.G. Hannum, M.J. Shlomchik, R. Ahmed. 2009. Requirement of B cells for generating CD4+ T cell memory. J. Immunol. 182: 1868-1876.
Whitmire, J.K. ♣, B. Eam, J.L. Whitton. 2009. Mice deficient in stem cell antigen-1 (Sca1, Ly-6A/E) develop normal primary and memory CD4+ and CD8+ T-cell responses to virus infection. Eur. J. Immunol. 39: 1494-1504.
Kemball, C.C., S. Harkins, J.K. Whitmire, C.T. Flynn, R. Feuer, J.L. Whitton. 2009. Coxsackievirus B3 Inhibits Antigen Presentation In Vivo, Exerting a Profound and Selective Effect on the MHC Class I Pathway. PloS-Pathog. 5(10): e1000618. doi:10.1371/journal.ppat.1000618.
Iannacone, M., G. Sitia, M. Isogawa, J.K. Whitmire, P. Marchese, F.V. Chisari, Z.M. Ruggeri, L.G. Guidotti. 2008. Platelets prevent IFN-alpha/beta-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. PNAS 105: 629-634.
Whitmire, J.K., N. Benning, B. Eam, and J.L. Whitton. 2008. Increasing the CD4+ T cell precursor frequency leads to competition for IFN, thereby degrading memory cell quantity and quality. J. Immunol. 180: 6777-6785.
Whitmire, J.K., B. Eam, J.L. Whitton. 2008. Tentative T cells: memory cells are quick to respond, but slow to divide. PloS Pathog. 4: e1000041.
Whitmire, J.K., B. Eam, N. Benning, J.L. Whitton. 2007. Direct interferon-γ signaling dramatically enhances CD4+ and CD8+ T cell memory. J. Immunol. 179: 1190-1197.
Zhang, B., C.H. Maris, J. Foell, J. Whitmire, L. Niu, J. Song, B.S. Kwon, A.T. Vella, R. Ahmed, J. Jacob, and R.S. Mittler. 2007. CD137 T cell costimulation-induced immune suppression or enhanced immune function during acute viral infection: timing is everything. J. Clin. Invest. 117: 3029-3041.
Whitmire, J.K., N. Benning, and J.L. Whitton. 2006. Precursor frequency, nonlinear proliferation, and functional maturation of virus-specific CD4+ T cells. J. Immunol. 176: 3028-3036.
Whitmire, J.K., J.T. Tan, and J.L. Whitton. 2005. Interferon-γ acts directly on CD8+ T cells to increase their abundance during virus infection. J. Exp. Med. 201: 1053-1059.
Whitmire, J.K., N. Benning, and J.L. Whitton. 2005. Cutting Edge: Early IFN-γ signaling directly enhances primary antiviral CD4+ T cell responses. J. Immunol. 175: 5624-5628.