Maintenance of T cell homeostasis is critical for normal functioning of the immune system. After thymocyte selection, T cells enter the peripheral lymphoid organs and are maintained there as naive cells. Transient disruption of homeostasis occurs when naive T cells undergo antigen-driven expansion and acquire effector functions. Effector T cells then either undergo apoptosis (i.e., contraction at the population level) or survive to become memory cells. This process is crucial: it resets T cell homeostasis, promotes protective immunity, and limits autoimmunity. While both pathways of apoptosis (death receptor and Bcl-2 regulated) can affect T cell homeostasis, recent data point to the Bcl-2-regulated pathway, under dynamic regulation by common gamma chain cytokines, as being critical for T cell homeostasis in vivo. Bim is a non-redundant, pro-apoptotic BH-3-containing molecule critical for limiting survival of naive, effector, and to a lesser extent memory T cells. However, the mechanism(s) by which effector T cells survive and enter the memory compartment remain unclear. Such knowledge is crucial for our ability to therapeutically manipulate the metamorphosis of effector T cells to memory T cells. We have found that as cells transition through stages of activation, the anti-apoptotic Bcl-2 family members critical for combating Bim appear to change. In naive and resting memory T cells, Bcl-2 is critical to antagonize Bim and promote survival. In situations where Bcl-2 is decreased or absent, Mcl-1 likely antagonizes Bim, but does so less efficiently than Bcl-2. Collectively, these new preliminary data suggest a model in which cytokine-driven signals through Stat5 to Bcl-2 and/or Mcl-1 modulate susceptibility of effector T cells to Bim-mediated death. A testable prediction of this model is that cytokine-driven antagonism of Bim should drive effector T cell survival and enhance pathogen clearance. Experiments in this proposal will test three interrelated hypotheses: (i) Mcl-1 antagonizes Bim in effector T cells when Bcl-2 levels are low (ii) depending upon the cytokine milieu Stat5 signaling to Bcl-2 and/ or Mcl-1 is critical for survival of effector T cells in vivo;and (iii) enhancement of cytokine availability can lead to increased effector T cell survival and pathogen clearance. The long-term goal of this research is to identify molecular targets that could be exploited therapeutically to enhance T cell survival (i.e. to improve vaccination) or to decrease T cell survival (i.e. suppress autoimmune disease or transplant rejection).

Public Health Relevance

Maintenance of T cell homeostasis is critical for normal functioning of the immune system. After an infection, the majority of T cells that have fought the infection die, while some remain, become """"""""memory"""""""" cells, and provide protection from re-infection. Mechanisms that control the death/survival of these T cells remain unclear, but are critical to our understanding of protective immunity. We have found that a single molecule Bim limits the numbers of memory T cells in mice. This proposal explores mechanism(s) by which T cells normally combat Bim and how they can be manipulated to combat Bim to improve immunologic memory.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057753-06
Application #
7990436
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Leitner, Wolfgang W
Project Start
2003-12-01
Project End
2013-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
6
Fiscal Year
2011
Total Cost
$369,877
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Ladle, Brian H; Li, Kun-Po; Phillips, Maggie J et al. (2016) De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8+ T-cell fate decisions following activation. Proc Natl Acad Sci U S A 113:10631-6
Kurtulus, S; Sholl, A; Toe, J et al. (2015) Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins. Cell Death Differ 22:174-84
Niss, Omar; Sholl, Allyson; Bleesing, Jack J et al. (2015) IL-10/Janus kinase/signal transducer and activator of transcription 3 signaling dysregulates Bim expression in autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol 135:762-70
Sena, Laura A; Li, Sha; Jairaman, Amit et al. (2013) Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38:225-36
Tripathi, P; Koss, B; Opferman, J T et al. (2013) Mcl-1 antagonizes Bax/Bak to promote effector CD4(+) and CD8(+) T-cell responses. Cell Death Differ 20:998-1007
Kurtulus, Sema; Hildeman, David (2013) Assessment of CD4(+) and CD8 (+) T cell responses using MHC class I and II tetramers. Methods Mol Biol 979:71-9
Raynor, Jana; Lages, Celine S; Shehata, Hesham et al. (2012) Homeostasis and function of regulatory T cells in aging. Curr Opin Immunol 24:482-7
Kurtulus, Sema; Tripathi, Pulak; Hildeman, David A (2012) Protecting and rescuing the effectors: roles of differentiation and survival in the control of memory T cell development. Front Immunol 3:404
Chougnet, Claire A; Tripathi, Pulak; Lages, Celine S et al. (2011) A major role for Bim in regulatory T cell homeostasis. J Immunol 186:156-63
Doetschman, Thomas; Sholl, Allyson; Chen, Hwu dau rw et al. (2011) Divergent effects of calcineurin Aβ on regulatory and conventional T-cell homeostasis. Clin Immunol 138:321-30

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