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).
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.
|McNally, Jonathan P; Millen, Scott H; Chaturvedi, Vandana et al. (2017) Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases. Proc Natl Acad Sci U S A 114:E4782-E4791|
|Li, Kun-Po; Fähnrich, Anke; Roy, Eron et al. (2017) Temporal Expression of Bim Limits the Development of Agonist-Selected Thymocytes and Skews Their TCR? Repertoire. J Immunol 198:257-269|
|Tripathi, Pulak; Morris, Suzanne C; Perkins, Charles et al. (2016) IL-4 and IL-15 promotion of virtual memory CD8+ T cells is determined by genetic background. Eur J Immunol 46:2333-2339|
|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|
|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|
|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|
|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|
Showing the most recent 10 out of 28 publications