Toll-like receptors (TLRs) play an integral role in innate and adaptive immunity. Ligation of TLRs activates cells of the innate immune system, inducing functions such as phagocytosis and IFN-a and IFN-b secretion. TLR-ligation also serves as a bridge between the innate and adaptive immune systems. TLR stimulation of DCs and macrophages induces the production of inflammatory cytokines such as IL-12, and upregulation of MHC class II and costimulatory ligands such as CD40 and CD86, and most of these responses require signals delivered through the adaptor signaling molecule MyD88. While roles for TLRs and MyD88 on APCs are well-established, surprisingly little is known about their expression and potential function on T cells. Studies from our laboratory show that several TLRs are expressed following activation of naive CD4+CD25 T cells. Ligation of these TLRs activates, via MyD88, several downstream signaling pathways, including NF- kB, p38 JNK, and ERK. Functionally, this leads to enhanced T cell survival and provides costimulation with sub-optimal TCR ligation. New data also indicates that in vivo expression of MyD88 in T cells may be required for a protective immune response to the pathogen Toxoplasma gondii. Our working hypothesis is that TLR and MyD88 signaling on T cells are important contributors to cellular immune responses. To this end, the long-term goals of this research program are to define the expression and function of TLRs on T cells.
In specific aim #1 we will characterize the signals which govern the expression and upregulation of TLRs on T cells, and the downstream signaling pathways which TLRs and MyD88 use to mediate their effects.
Specific aim #2 will use cells from TCR transgenic mice coupled with in vitro and in vivo adoptive transfer systems to conduct a detailed examination of the effects of TLR and MyD88 activation of T cells on induction of activation and costimulatory molecules, cytokine production or skewing, and effector/memory differentiation and responsiveness. This approach will allow for precise definition of what TLR stimulation of T cells can do.
In specific aim #3 we will then ask which of the functions identified for TLRs and MyD88 in aim #2 are operative during in vivo immune responses. To do so, we will use MyD88 knockout mice and bone-marrow chimeras and adoptive transfer systems to create in vivo models in which only T cells are deficient in MyD88. Based on our preliminary data, we will use these models to assess responses to Toxoplasma gondii, and will also backcross the MyD88-deficient mice onto TCR transgenic backgrounds to enable us to track the fate of individual T cells as they respond to alloantigen in vivo in transplantation models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI062789-01A1
Application #
7033777
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Nabavi, Nasrin N
Project Start
2006-01-01
Project End
2010-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
1
Fiscal Year
2006
Total Cost
$353,250
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Rahman, Adeeb H; Zhang, Ruan; Blosser, Christopher D et al. (2011) Antiviral memory CD8 T-cell differentiation, maintenance, and secondary expansion occur independently of MyD88. Blood 117:3123-30
Rahman, Adeeb H; Taylor, Devon K; Turka, Laurence A (2009) The contribution of direct TLR signaling to T cell responses. Immunol Res 45:25-36
Rahman, Adeeb H; Cui, Weiguo; Larosa, David F et al. (2008) MyD88 plays a critical T cell-intrinsic role in supporting CD8 T cell expansion during acute lymphocytic choriomeningitis virus infection. J Immunol 181:3804-10
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LaRosa, David F; Stumhofer, Jason S; Gelman, Andrew E et al. (2008) T cell expression of MyD88 is required for resistance to Toxoplasma gondii. Proc Natl Acad Sci U S A 105:3855-60
LaRosa, David F; Rahman, Adeeb H; Turka, Laurence A (2007) The innate immune system in allograft rejection and tolerance. J Immunol 178:7503-9
Dzierszinski, Florence; Pepper, Marion; Stumhofer, Jason S et al. (2007) Presentation of Toxoplasma gondii antigens via the endogenous major histocompatibility complex class I pathway in nonprofessional and professional antigen-presenting cells. Infect Immun 75:5200-9
Yang, Jaeseok; Brook, Matthew O; Carvalho-Gaspar, Manuela et al. (2007) Allograft rejection mediated by memory T cells is resistant to regulation. Proc Natl Acad Sci U S A 104:19954-9
LaRosa, David F; Gelman, Andrew E; Rahman, Adeeb H et al. (2007) CpG DNA inhibits CD4+CD25+ Treg suppression through direct MyD88-dependent costimulation of effector CD4+ T cells. Immunol Lett 108:183-8

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