Steven L. Reiner, M.D.
Immunity is a problem of regeneration, and fundamentally a balancing act
To kill a cancerous or virally infected cell, a quiescent T lymphocyte must be activated to grow, divide, and produce differentiated cellular progeny, often again and again. Essentially, lymphocytes must achieve the mutually opposing demands of differentiation and self-renewal, regeneration. How T lymphocytes accomplish the paradoxical tasks of changing while remaining the same has been enigmatic.
Our recent discoveries have indicated that lymphocyte activation is an inherently semi-conservative signaling process during cell division. When a quiescent naive or memory T cell is activated, one daughter cell becomes a highly activated progenitor, while its sibling cell remains more quiescent. Analogously, when the activated progenitor undergoes more antigenic activation, one of its daughter cells irreversibly differentiates, while its sibling cell remains an active progenitor. The asymmetric cell divisions that give rise to activated versus quiescent sibling cells, or differentiated versus self-renewing sibling cells both seem to depend on the capacity of nutritive phosphatidylinositol-3-kinase (PI3K) signaling to direct polarity of the very receptors that deliver PI3K-mediated signals for cell division and differentiation.
Immune regeneration exploits the dichotomy of feast and famine
Single-celled organisms evolved to maintain the species in one of two mutually opposing ways, cell duplication or dormant survival, a decision that rests on the availability or scarcity of nutrients surrounding them. T lymphocytes appear to exploit this evolutionarily conserved metabolic switch to balance differentiation and renewal by transmitting unequal anabolic PI3K signals to daughter cells during cell division. A cell with limited nutrient uptake self-digests and generates energy in the most efficient manner possible; it does not waste energy preparing for cell division. Conversely, abundant nutrient uptake signals cells to focus on macromolecular synthesis, not energy efficiency, and instructs them not to self-digest. The mutually opposing signaling circuitry of feast and famine, together with a mechanism that transmits signaling unequally during cell division allows sibling T cells to become more and less activated, and subsequently fully and less differentiated, the balancing act of regeneration.
Implications for cancer immunotherapy
Because T cell activation promotes differentiation, we are testing the hypothesis that inhibitory signaling of T cells promotes self-renewal. A further prediction of this hypothesis is that blockade of inhibitory signaling might promote greater differentiation and function but at the expense of self-renewal and durability of critical T cell clones. We are currently testing whether blockade of immune checkpoints and expansion protocols for adoptive cell therapy can achieve better durability if agents that promote self-renewal of T cells, particularly those with anti-anabolic properties, are added to standard protocols.
Postdoctoral Positions Available (contact Dr. Reiner)
Immuno-oncology, immuno-metabolism, infectious diseases, self-renewal, immunological memory, cell signaling and polarity, T and B lymphocyte fate and function.
- Kratchmarov, R., Magun, A.M. and Reiner, S.L. (2018) TCF1 expression marks self-renewing human CD8(+) T cells. Blood Adv. 2: 1685-1690.
- Yen, B., Fortson, K.T., Rothman, N.J., Arpaia, N. and Reiner, S.L. (2018) Clonal bifurcation of Foxp3 expression visualized in thymocytes and T cells. Immunohorizons 2: 119-128.
- Kratchmarov, R., Viragova, S., Kim, M.J., Rothman, N.J., Liu, K., Reizis, B. and Reiner, S.L. (2018) Metabolic control of cell fate bifurcations in a hematopoietic progenitor population. Immunol. Cell Biol. doi: 10.1111/imcb.12040. [Epub ahead of print]
- Chen, Y.H., Kratchmarov, R., Lin, W.W., Rothman, N.J., Yen, B., Adams, W.C., Nish, S.A., Rathmell, J.C. and Reiner, S.L. (2018) Asymmetric PI3K activity in lymphocytes organized by a PI3K-mediated polarity pathway. Cell Rep. 22: 860-868.
- Kratchmarov, R., Nish, S.A., Lin, W.W., Adams, W.C., Chen, Y.H., Yen. B,, Rothman, N.J., Klein, U. and Reiner, S.L. (2017) IRF4 couples anabolic metabolism to Th1 cell fate determination. Immunohorizons 1: 156-161.
- Nish, S.A., Lin, W.W. and Reiner, S.L. (2017) Lymphocyte fate and metabolism: A clonal balancing act. Trends Cell Biol. 27: 946-954.
- Collins, A., Rothman, N., Liu, K. and Reiner, S.L. (2017) Eomesodermin and T-bet mark developmentally distinct human natural killer cells. JCI Insight 2: e90063.
- 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.
- Lin, W.W., Nish, S.A., Yen, B., Chen, Y.H., Adams, W.C., Kratchmarov, R., Rothman, N.J., Bhandoola, A., Xue, H.H. and Reiner, S.L. (2016) CD8+ T lymphocyte self-renewal during effector cell determination. Cell Rep. 17: 1773-1782.
- 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. and Adams, W.C. (2014) Lymphocyte fate specification as a deterministic but highly plastic process. Nature Rev. Immunol. 14: 699-704.
- 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.
- 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.
- 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., 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.
- 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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