While it is relatively easy to induce long-term tolerance in rodent models, translation of these protocols to higher vertebrates and clinical medicine has been difficult. Unlike mice, humans are constantly exposed to viral pathogens which induce transient lymphopenia and the generation of immune memory. A known barrier to transplant in humans is a large number of alloreactive memory T cells, even in those individuals without previous exposure to alloantigen. Proposed mechanisms for the generation of alloreactive memory T cells in the absence of alloantigen include cross-reactivity following acute or chronic viral infection in a process termed heterologous immunity and through homeostatic expansion in response to lymphopenia. Understanding the signals that allow alloreactive memory T cells to persist long-term may suggest new strategies for clinical tolerance. Homeostasis of memory T cells is mediated through a combination of long-term survival of individual cells and cell turnover. These two processes are controlled via extracellular signals recognized by the clonotypic T cell receptor (TCR) and cytokine receptors. The relative contribution of TCR signals and cytokine receptor generated signals may vary depending on the nature of the immunogen, however the specific intracellular signaling pathways required for homeostasis have not been well defined. The overriding hypothesis of this proposal is that the T cell receptor mediated signaling requirements for memory T cell homeostasis and for heterologous immunity differ depending on whether a memory cell is generated by acute viral infection, by chronic viral infection, or antigen-independent events. To address this hypotheses, we have developed a novel in vivo murine model which allows temporally controlled genetic deletion in memory T cells of a key proximal signaling molecule downstream of TCR signaling, the SH2 domain containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76). SLP-76 conditionally deficient T cells offer a unique model for studying memory T cells that were generated with an intact TCR signaling apparatus but lack the ability to transduce either antigen-specific or tonic TCR signals. Our preliminary data show that in contrast to non-manipulated memory phenotype T cells, SLP-76 deficient memory phenotype T cells fail to undergo homeostatic division in an intact host. We propose to define and dissect the effect of infection on homeostasis of memory T cells and transplantation by combining viral infection models with conditional gene deletion and studies on transplantation tolerance.

Public Health Relevance

Immune memory is a hallmark of adaptive immune system and conveys the ability to respond faster and better when an individual is infected for a second time with the same infectious agent (i.e. virus). Immune memory requires infection-specific white blood cells termed lymphocytes to persist for the life of the individual in the absence of ongoing infection. Due of cross-reactivity of some memory T cells, previous viral infection can result in worse outcomes in experimental transplantation of solid organs. The goals of this application are to better understand how memory T cells that are made to fight off infection can adversely affect transplantation and persist to provide long-term immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085160-03
Application #
8264562
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Lapham, Cheryl K
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$385,313
Indirect Cost
$137,813
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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Wu, Gregory F; Corbo, Evann; Schmidt, Michelle et al. (2011) Conditional deletion of SLP-76 in mature T cells abrogates peripheral immune responses. Eur J Immunol 41:2064-73
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