Steven L. Reiner, M.D.
Upon engagement in an immune response, a naive T lymphocyte undergoes a program of rapid proliferation and many of its cellular progeny undergo terminal effector differentiation. After an immune response has ended, some antigen-specific daughter cells remain as long-lived replicas of the useful clone, so-called memory cells, which form the basis for successful vaccination. Using lymphocytes as a model system, we have provided evidence that asymmetric cell division may be a way for many mobile, non-polarized cells to generate cell fate diversity among their progeny. We are using static and time-lapsed imaging, genetic, and biochemical methods to better understand the nature and extent of asymmetric cell division in multi-celled beings. It is predicted that this will have immediate relevance for the way in which blood stem cells and metastatic cancer stem cells can generate diverse progeny despite their lack of obvious polarity. Studies of lymphocyte differentiation during the immune response should continue to become an increasingly useful model for inquiry into the fundamental problem of regulated gene expression in dividing, differentiating, and highly mobile cells.
Asymmetric cell division; stem cell self-renewal; epigenetic and transcription factor-mediated control of gene expression; host response to infection and cancer; effector and memory T lymphocyte differentiation
- Nish, S.A., Zens, K.D., Kratchmarov, R., Lin, W.W., Adams, W.C., Chen, Y.H., Yen, B., Rothman, N.J., Bhandoola, A., Xue, H.H., Farber, D.L. and Reiner, S.L. (2017) CD4+ T cell effector commitment coupled to self-renewal by asymmetric cell divisions. J. Exp. Med. 214: 39-47.
- Adams, W.C., Chen, Y.H., Kratchmarov, R., Yen, B., Nish, S.A., Lin, W.W., Rothman, N.J., Luchsinger, L.L., Klein, U., Busslinger, M., Rathmell, J.C., Snoeck, H.W. and Reiner, S.L. (2016) Anabolism-associated mitochondrial stasis driving lymphocyte differentiation over self-renewal. Cell Rep. 17: 3142-3152.
- Pikovskaya, O., Chaix, J., Rothman, N.J., Collins, A., Chen, Y.H., Scipioni, A.M., Vivier, E. and Reiner, S.L. (2016) Cutting Edge: Eomesodermin is sufficient to direct Type 1 innate lymphocyte development into the conventional NK lineage. J. Immunol. 197: 1017-1022.
- Lin, W.H., Adams, W.C., Nish, S.A., Chen, Y.H., Yen, B., Rothman, N.J., Kratchmarov, R., Okada, T., Klein, U. and Reiner, S.L. (2015) Asymmetric PI3K signaling driving developmental and regenerative cell fate bifurcation. Cell Rep. 13: 2203-2218.
- Reiner, S.L. (2015) T-bet transcendent: unmasking the faces of multifarious immunity. J. Immunol. 194: 2959-2960.
- Harms Pritchard, G., Hall, A.O., Christian, D.A., Wagage, S., Fang, Q., Muallem, G., John, B., Glatman Zaretsky, A., Dunn, W.G., Perrigoue, J., Reiner, S.L. and Hunter, C.A. (2015) Diverse roles for T-bet in the effector responses required for resistance to infection. J. Immunol. 194: 1131-1140.
- Reiner, S.L. and Adams, W.C. (2014) Lymphocyte fate specification as a deterministic but highly plastic process. Nature Rev. Immunol. 14: 699-704.
- Chaix, J., Nish, S.A., Lin, W.H., Rothman, N.J., Ding, L., Wherry, E.J. and Reiner, S.L. (2014) Cutting edge: CXCR4 is critical for CD8+ memory T cell homeostatic self-renewal but not rechallenge self-renewal. J. Immunol. 193: 1013-1016.
- Paley, M.A., Gordon, S.M., Bikoff, E.K., Robertson, E.J., Wherry, E.J. and Reiner, S.L. (2013) Technical Advance: Fluorescent reporter reveals insights into eomesodermin biology in cytotoxic lymphocytes. J. Leukoc. Biol. 93: 307-315.
- Paley, M.A., Kroy, D.C., Odorizzi, P.M., Johnnidis, J.B., Dolfi, D.V., Barnett, B.E., Bikoff, E.K., Robertson, E.J., Lauer, G.M., Reiner, S.L. and Wherry, E.J. (2012) Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338: 1220-1225.
- Ciocca, M.L., Barnett, B.E., Burkhardt, J.K., Chang, J.T. and Reiner, S.L. (2012) Cutting Edge: Asymmetric memory T cell division in response to rechallenge. J. Immunol. 188: 4145-4148.
- Gordon, S.M., Chaix, J., Rupp, L.J., Wu, J., Madera, S., Sun, J.C., Lindsten, T. and Reiner, S.L. (2012) The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 36: 55-67.
- Barnett, B.E., Ciocca, M.L., Goenka, R., Barnett, L.G., Wu, J., Laufer, T.M., Burkhardt, J.K., Cancro, M.P. and Reiner, S.L. (2012) Asymmetric B cell division in the germinal center reaction. Science 335: 342-344.
- Chang, J.T., Ciocca, M.L., Kinjyo, I., Palanivel, V.R., McClurkin, C.E., Dejong, C.S., Mooney, E.C., Kim, J.S., Steinel, N.C., Oliaro, J., Yin, C.C., Florea, B.I., Overkleeft, H.S., Berg, L.J., Russell, S.M., Koretzky, G.A., Jordan, M.S. and Reiner, S.L. (2011) Asymmetric proteasome segregation as a mechanism for unequal partitioning of the transcription factor T-bet during T lymphocyte division. Immunity 34: 492-504.
- Banerjee, A., Gordon, S.M., Intlekofer, A.M., Paley, M.A., Mooney, E.C., Lindsten, T., Wherry, E.J. and Reiner, S.L. (2010) Cutting Edge: The transcription factor Eomesodermin enables CD8+ T cells to compete for the memory cell niche. J. Immunol. 185: 4988-4992.
- Kinjyo, I., Gordon, S.M., Intlekofer, A.M., Dowdell, K., Mooney, E.C., Caricchio, R., Grupp, S.A., Teachey, D.T., Rao, V.K., Lindsten, T. and Reiner, S.L. (2010) Cutting Edge: Lymphoproliferation caused by fas deficiency is dependent on the transcription factor eomesodermin. J. Immunol. 185: 7151-7155.
- Intlekofer, A.M., Banerjee, A., Takemoto, N., Gordon, S.M., Dejong, C.S., Shin, H., Hunter, C.A., Wherry, E.J., Lindsten, T. and Reiner, S.L. (2008) Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science 321: 408-411.
- Chang, J.T., Palanivel, V.R., Kinjyo, I., Schambach, F., Intlekofer, A.M., Banerjee, A., Longworth, S.A., Vinup, K.E., Mrass, P., Oliaro, J., Killeen, N., Orange, J.S., Russell, S.M., Weninger, W. and Reiner, S.L. (2007) Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315: 1687-1691.
- Intlekofer, A.M., Takemoto, N., Kao, C., Banerjee, A., Schambach, F., Northrop, J.K., Shen, H., Wherry, E.J. and Reiner, S.L. (2007) Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells. J. Exp. Med. 204: 2015-2021.
- Takemoto, N., Intlekofer, A.M., Northrup, J.T., Wherry, E.J. and Reiner, S.L. (2006) Cutting Edge: IL-12 inversely regulates T-bet and eomesodermin expression during pathogen-induced CD8+ T cell differentiation. J. Immunol. 177: 7515-7519.
- Intlekofer, A.M., Takemoto, N., Wherry, E.J., Longworth, S.A., Northrup, J.T., Palanivel, V.R., Mullen, A.C., Gasink, C.R., Kaech, S.M., Miller, J.D., Gapin, L., Ryan, K., Russ, A.P., Lindsten, T., Orange, J.S., Goldrath, A.W., Ahmed, R. and Reiner, S.L. (2005) Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nature Immunology 6: 1236-1244.
- Pearce, E.L., Mullen, A.C., Martins, G.A., Krawczyk, C.M., Hutchins, A.S., Zediak, V.P., Banica, M., DiCioccio, C.B., Gross, D.A., Mao, C.A., Shen, H., Cereb, N., Yang, S.Y., Lindsten, T., Rossant, J., Hunter, C.A. and Reiner, S.L. (2003) Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 302: 1041-1043.
- Hutchins, A.S., Mullen, A.C., Lee, H.W., Sykes, K.J., High, F.A., Hendrich, B.D., Bird, A.P. and Reiner, S.L. (2002) Gene silencing quantitatively controls the function of a developmental trans-activator. Mol. Cell 10: 81-91.
- Mullen, A.C., Hutchins, A.S., High, F.A., Lee, H.W., Sykes, K.J., Chodosh, L.A. and Reiner, S.L. (2002) Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction. Nature Immunology 3: 652-658.
- Mullen, A.C., High, F.A., Hutchins, A.S., Lee, H.W., Villarino, A.V., Livingston, D.M., Kung, A.L., Cereb, N., Yao, T.P,. Yang, S.Y. and Reiner, S.L. (2001) Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292: 1907-1910.
- Bird, J.J., Brown, D.R., Mullen, A.C., Moskowitz, N.H., Mahowald, M.A., Sider, J.R., Gajewski, T.F., Wang, C.R. and Reiner, S.L. (1998) Helper T cell differentiation is controlled by the cell cycle. Immunity 9: 229-237.
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