Our laboratory is interested in the immunological basis for the control of infection and pathology associated with complex viral pathogens. Our principal focus has been HSV-1, which infects mucocutaneous epithelial cells and sensory neurons, and causes a lifelong latent infection in the nervous system. Our current focus is the role of the innate and acquired immune responses involved in resisting HSV-1 infection, and how these two components of immunity interact with each other to generate optimal protective responses.
Analysis of HSV-1-specific CD8+ T cell responses.
We have focused upon the events resulting in a potent, protective CD8+ T cell response against cutaneous HSV-1 infections. We have defined the kinetics of CD8+ T cell activation and the acquisition of effector function by this subpopulation. We know that two subpopulations of HSV-1-specific CD8+ T cells are generated during the initial response to infection: one expressing high levels of CD25 (IL-2 receptor α-chain); and a second population expressing low levels of CD25. Our current studies are investigating the relative contribution of each subpopulation to the control of infection in the skin and nervous system, their relationship to each other, the role of IL-2 and IL-15 in their development, and the contribution of each to long-term HSV-1-specific CD8+ T cell memory. Current studies also focus on the ability of HSV-1-specific CD8+ T cells to limit infection of the central nervous system from peripheral sites.
Analysis of the immunological basis for resistance to cutaneous HSV-1 infection.
Similar to human patients infected with HSV-1 and/or HSV-2, inbred mouse strains exhibit a spectrum of susceptibility to cutaneous HSV infection. The ability to resist cutaneous HSV-1 is associated with rapid synthesis of type I IFNs (IFN-α/β) and early activation of natural killer (NK) cells, and viral clearance is dependent upon HSV-1-specific T cells. Our recent studies have focused upon the role of dendritic cells (DCs) in the intrinsic resistance to HSV-1 and determined that DCs are crucial for preventing lethal infection of the central nervous system. We are currently working on the hypothesis that certain DC subpopulations synthesize high levels of type I IFNs, which in turn activate NK cells and T cells to optimal activity. We are also investigating the role of particular HSV-1 genes to determine their role in HSV-1-mediated impairment of DC function in vivo. These studies have led to investigations of the role of certain Toll-like pattern recognition receptors (TLRs) in the innate and adaptive immune responses, and their role in limiting HSV-1 replication and spread within the peripheral and central nervous systems.
Selected Publications (See all Stephen Jennings's publications in PubMed.)
"CD4+ T cells are required for priming of CD8+ T cells following infection with herpes simplex virus type -1"
Rajasagi NK, Kassim SH, Zhao X, Chervenak R, and Jennings SR
Journal of Virology, 83: 5256-5268, 2009
"Dendritic cells are required for optimal activation of natural killer functions following primary infection with herpes simplex virus type-1 (HSV-1)"
Kassim SH, Rajasagi NK, Ritz B, Pruett SB, Chervenak R, and Jennings SR
Journal of Virology, 83: 3175-3186, 2009
"Memory CD8+ T cells require CD28 costimulation"
Borowski AB, Boesteanu AC, Mueller YM, Carafides C, Topham DJ, Altman JD, Jennings SR, and Katsikis PD
The Journal of Immunology, 179(10): 6494-6503, 2007
"Modulation of dendritic cell maturation and functions by the Tax protein of human T cell leukemia virus type 1: implications for viral neuropathogenesis"
Jain P, Ahuja J, Khan ZK, Shimzu S, Meucci O, Kampani K, Jennings SR, and Wighdahl B
Journal of Leukocyte Biology, 82: 44-56, 2007
"In vivo ablation of CD11c-positive dendritic cells increases susceptibility to HSV-1 infection and hampers the NK and T cell responses"
Kassim SH, Rajasagi NK, Zhao X, Chervenak R, and Jennings SR
Journal of Virology, 80: 3985-3993, 2006
"Cytokine Profiles and Long Term Virus-Specific Antibodies following Immunization of CBA Mice with Equine Herpesvirus 1 and Viral Glycoprotein D"
Zhang Y, Smith PM, Frampton AR, Osterrieder N, Jennings SR, and O'Callaghan DJ
Viral Immunology, 16: 307-320, 2003
"Interferon-gamma and interleukin-10 reciprocally regulate endothelial junction integrity and barrier function"
Oshima T, Laroux FS, Coe LL, Morise Z, Kawachi S, Bauer P, Grisham MB, Specian RD, Carter P, Jennings SR, "Granger DN, Joh T, and Alexander JS
Microvascular Research, 61: 130-143, 2000
"Expression of endothelial cell adhesion molecules in neovascularized tissue"
Vallien G, Langley R, Jennings SR, Specian R, and Granger DN
Microcirculation, 7: 249-258, 2000
"Severe immunopathology in the murine lung elicited by the pathogenic EHV-1 strain RacL11 correlates with the early production of MIP-1a, MIP-1b, MIP-2 and TNF-a"
Smith PM, Zhang YF, Grafton WD, Jennings SR, and O'Callaghan DJ
Journal of Virology, 74: 10034-10040, 2000
"Cytokine and adhesion molecule expression in SCID mice reconstituted with CD4+ T cells"
Kawachi S, Morise Z, Jennings SR, Conner E, Cockrell A, Laroux FS, Chervenak R, Wolcott M, van der Heyde H, Gray L, Feng L, Granger N, Specian RD, and Grisham MB
Inflammatory Bowel Disease, 6: 171-180, 2000
"Expression of intracellular interferon-g in HSV-1-specific CD8-positive T cells identifies distinct responding subpopulations during the primary response to infection"
Andersen H, Dempsey D, Chervenak R, and Jennings SR
The Journal of Immunology, 165: 2101-2107, 2000
"Determination of specific antibody-secreting cells following immunization with EHV-1 KyA and recombinant glycoprotein D by ELISPOT in CBA mice"
Zhang YF, Smith PM, Jennings SR, and O'Callaghan DJ
Virology, 268: 482-492, 2000
"Diminished secondary CTL response in draining lymph nodes on cutaneous challenge with herpes simplex virus"
Jones CM, Cose SC, McNally JM, Jennings SR, Heath WR, and Carbone FR
Journal of General Virology, 81: 407-414, 2000
"Phenotypic characteristics associated with the acquisition of HSV-specific CD8 T-lymphocyte-mediated cytolytic function in vitro"
McNally JM, Andersen HA, Chervenak R, and Jennings SR
Cellular Immunology, 194: 103-111, 1999
"Phenotypic identification of antigen-dependent and antigen-independent CD8 CTL precursors in the draining lymph node during acute cutaneous herpes simplex virus type 1 infection"
McNally JM, Dempsey D, Wolcott RM, Chervenak R, and Jennings SR
The Journal of Immunology, 163: 675-681, 1999