Steven L. Reiner, M.D.

Charles H. Revson Professor of Microbiology & Immunology and Pediatrics
M.D., Duke University

T cell immunity to cancer and infection

Research

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 discoveries have indicated that lymphocyte activation induces asymmetric cell division, allowing an antigen-specific lymphocyte progenitor to yield one daughter cell that irreversibly differentiates, while its sibling cell remains less differentiated, capable of both self-renewing and giving rise to fully functional cells.

Implications for immunotherapy
T lymphocytes appear to exploit an evolutionarily conserved metabolic switch to balance differentiation and renewal by transmitting unequal anabolic PI3K signals to daughter cells during cell division. 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.

Research Interests
Immuno-oncology, immuno-metabolism, infectious diseases, asymmetric cell division, immunological memory, cell signaling and polarity, lymphocyte fate and function

Selected Publications

1. Reiner S.L. (2025) Immune regeneration: implications for cancer immunotherapy and beyond. J. Clinical Invest. 135: e192731. https://doi.org/10.1172/JCI192731

2. Wang, P.H., Washburn, R.S., Mariuzza, D.L., Lin, W.W., Gill, A.L., Ahmed, R. and Reiner, S.L. (2023) Reciprocal transmission of activating and inhibitory signals and cell fate in regenerating T cells. Cell Reports 42: 113155. https://doi.org/10.1016/j.celrep.2023.113155

3. Gill, A. L., Wang, P. H., Lee, J., Hudson, W. H., Ando, S., Araki, K., Hu, Y., Wieland, A., Im, S., Gavora, A., Medina, C. B., Freeman, G. J., Hashimoto, M., Reiner, S. L. and Ahmed, R. (2023). PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors. Science Immunology 8: eadg0539. https://doi.org/10.1126/sciimmunol.adg0539

4. Bukhari, S., Henick, B.S., Winchester, R.J., Lerrer, S., Adam, K., Gartshteyn, Y., Maniar, R., Lin, Z., Khodadadi-Jamayran, A., Tsirigos, A., Salvatore, M.M., Lagos, G.G., Reiner, S.L., Dallos, M.C., Mathew, M., Rizvi, N.A. and Mor, A. (2023) Single-cell RNA sequencing reveals distinct T cell populations in immune-related adverse events of checkpoint inhibitors. Cell Reports Medicine 4: 100868. https://doi.org/10.1016/j.xcrm.2022.100868

5. Maniar, R., Wang, P.H., Washburn, R.S., Kratchmarov, R., Coley, S.M., Saqi, A., Pan, S.S., Hu, J., Shu, C.A., Rizvi, N.A., Henick, B.S. and Reiner, S.L. (2023) Self-renewing CD8+ T-cell abundance in blood associates with response to immunotherapy. Cancer Immunol. Res. 11: 164–170. https://doi.org/10.1158/2326-6066.CIR-22-0524

6. Wang, P.H., Washburn, R., Maniar, R., Mu, M., Ringham, O., Kratchmarov, R., Henick, B.S. and Reiner, S.L. (2022) Cutting Edge: Promoting T cell factor 1+ T cell self-renewal to improve Programmed Cell Death Protein 1 blockade. J. Immunol. 209: 660–664. https://doi.org/10.4049/jimmunol.2200317

7. Johnnidis, J.B., Muroyama, Y., Ngiow, S.F., Chen, Z., Manne, S., Cai, Z., Song, S., Platt, J.M., Schenkel, J. M., Abdel-Hakeem, M., Beltra, J.C., Greenplate, A.R., Ali, M.A., Nzingha, K., Giles, J.R., Harly, C., Attanasio, J., Pauken, K. E., Bengsch, B., Paley, M.A., Tomov, V.T., Kurachi, M., Vignali, D.A.A., Sharpe, A.H., Reiner, S.L., Bhandoola, A., Johnson, F.B. and Wherry, E.J. (2021) Inhibitory signaling sustains a distinct early memory CD8+ T cell precursor that is resistant to DNA damage. Science Immunol. 6: eabe3702. https://doi.org/10.1126/sciimmunol.abe3702

8. Kratchmarov, R., Magun, A.M. and Reiner, S.L. (2018) TCF1 expression marks self-renewing human CD8(+) T cells. Blood Adv. 2: 1685-1690.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.