Homeostatic regulation of T lymphocytes is a central mechanism by which the immune system ensures its diversity and functionality. T cell deficiency triggers a proliferative response of T cells that remain within such conditions or that are adoptively transferred into such environments (which is often referred to as homeostatic proliferation or endogenous proliferation). The proliferation is often associated with a differentiation process that generates memory T cells. The resulting memory T cells are thought to play a critical role in the regulation of peripheral homeostasis as well as in the protection against invading pathogens.
There is substantial evidence suggesting that lymphopenia induced immune activation may result in autoimmunity, multiorgan immunopathology, as well as rejection of solid organ transplants. Therefore, understanding the mechanisms regulating T cell proliferation in lymphopenic conditions has fundamental biological importance. Our study aims at defining the mechanisms by which T cell proliferation/differentiation processes are induced and regulated.
How T cells are induced to proliferate without exogenous cognate Ag stimulation? Why it doesn't occur under non-lymphopenic conditions? We have recently reported that different subsets of APCs are involved in proliferation of T cell subsets; namely, naïve and memory CD4 T cell proliferation is completely dependent on interaction with MHC II molecules exclusively expressed on CD11c+ DCs. On the other hand, naïve CD8 T cell proliferation still occurs in the absence of MHC I. Surprisingly, CD8 T cells are capable of interacting with MHC II molecules when MHC I is absent. For details, see Do et al. PNAS (2009). We currently examine cellular mechanism that regulates proliferation in vivo. We are also interested in understanding the contribution of apoptosis of T cells during homeostatic regulation.
Recently, we became interested in gd T cell subsets that are specialized in producing IL-17 under non-inflammatory conditions. We identified that these IL-17+ gd T cells are primarily generated within the thymus during the postnatal period and that TGF b 1 plays the major role in the generation. However, cellular mechanism underlying the in vivo generation of IL-17+ gd T cells as well as their immunologic roles as 'innate IL-17-producers' remain poorly understood. We are actively pursuing this issue.
Another project that we recently initiated is to examine T cell homeostasis within nonlymphoid tissues, the CNS during acute and persistent virus infection. Our lab teamed with Drs. Steve Stohlman and Conni Bergmann (Neuroscience Dept, CCF), and investigate cellular mechanisms of T cell retention within the CNS during the JHMV infection. More specifically, we will determine whether viral Ag presentation induces CD8 T cell retention in the CNS during persistent infection. Moreover, we will test how CD4 T cells contribute to the survival and the retention of CD8 T cells in the CNS during persistent infection.
Last project that we investigate is to examine in vivo roles of basophils. Basophils have recently been studied by many investigators, and their roles as immune effectors as well as modulators continue to increase. We are particularly interested in mechanism that mobilizes circulating basophils into the lymphoid tissues. This will be an interesting topic because it is believed that basophils which that enter the LN promote the development of Th2 immune responses in vivo. However, we recently reported that it is not always the case; i.e., basophils may be dispensable for Th2 immunity under certain circumstances. We are in process of dissecting the processes of in vivo migration of circulating basophils and their participation during Th2-related immune responses.
Visperas, A., B. Shen, and B. Min. (2014). gd T cells restrain extrathymic development of Foxp3+ inducible regulatory T cells via IFNg. Eur. J. Immunol. In Press.
Do, J., K. Asosingh, and B. Min. (2014). Cutting Edge: IFNg signaling in non-T cell targets regulates T cell-mediated intestinal inflammation through multiple mechanisms. J. Immunol. In Press.
Visperas, A., J. Do, K. Bulek, X. Li, and B. Min. (2014). IL-27, targeting antigen presenting cells, enhances Th17 differentiation and inflammation by upregulating Th17 promoting cytokine production. Mucosal Immunol. Advanced online publication.
Do, J., A. Visperas, M. L. Freeman, Y. Iwakura, M. Oukka, and B. Min. (2014). Colitogenic effector T cells: roles of gut homing integrin, gut antigen specificity and gd T cells. Immunol. Cell. Biol. 92:90-98.
Rao, K. N., C. Smuda, G. D. Gregory, B. Min, and M. A. Brown. (2013). Ikaros limits basophil development by suppressing C/EBPa expression. Blood122:2572-2581.
Do, J., A. Valujskikh, D. A. A. Vignali, R. L Fairchild, and B. Min. (2012). An unexpected role for MHCII-peptide complexes in shaping CD8 T cell expansion and differentiation in vivo. Proc. Natl. Acad. Sci. USA 109:12698-12703.
Zizhen, K., S. Swaidani, W. Yin, C. Wang, J. L. Barlow, M. F. Gulen, K. Bulek, J. Do, M. Aronica, A. N. McKenzie, B. Min, and X. Li. (2012). Epithelial cell-specific Act1 adaptor mediates IL-25-dependent helminth expulsion through expansion of Lin(-)c-Kit(+) innate cell population. Immunity 36:821-833.
Phares, T. W., S. A. Stohlman, M. Hwang, B. Min, D. R. Hinton, and C. C. Bergmann. (2012). CD4 T cells promote CD8 T cell immunity at the priming and effector site during viral encephalitis. J. Virol. 86:2416-2427.
Do, J., G. Foucras, A. F. Schenk, M. Shaw, G. Nunez, W. E. Paul, and B. Min. (2012). Both exogenous commensal and endogenous self antigens stimulate T cell proliferation under lymphopenic conditions. Cell. Immunol. 272:117-123.
Do, J., A. Visperas, R. L. O’brien, and B. Min. (2012). CD4 T cells enhance the generation of IL-17+ gd T cells. Immunol. Cell. Biol. 90:396-403.
Do, J., A. Visperas, K. Oh, S. A. Stohlman, and B. Min. (2012). Memory CD4 T cells induce selective expression of IL-27 in CD8+ DC and regulate homeostatic naïve T cell proliferation. J. Immunol. 188:230-237.