Jafar Al Souz, Yulong Wei, Can Cui, Rihao Qu, Jin-Young Choi, F Wang, Steven J. Moioffer, Julia Barrett, Irene Chernova, Manvitha Nadella, Emily R. Siniscalco, Gilbert Moeckel, Nikhil S. Joshi, Ping-Min Chen, Arnon Arazi, Jennifer Anolik, William Apruzzese, Arnon Arazi, Jennifer Barnas, Michael Belmont, Celine Berthier, Michael B. Brenner, Jill Buyon, Phillip Carlucci, Robert Clancy, Sean Connery, Maria Dall’Era, Anne Davidson, Wade DeJager, Kristina Deonaraine, Betty Diamond, Patrick Dunn, Thomas Eisenhaure, Andrea Fava, Jennifer Goff, Béatrice Goilav, Jennifer Grossman, Joel Guthridge, Nir Hacohen, David A. Hildeman, Jeffery Hodgin, Paul Hoover, Raymond Hsu, Kazuyoshi Ishigaki, Mariko Ishimori, Peter Izmirly, Judith James, Tony Jones, Ken Kalunian, Diane L. Kamen, Ilya Korsunsky, Matthias Kretzler, Manjunath Kustagi, James Lederer, Jessica Li, David Lieb, Susan Macwana, Holden Maecker, Rong Mao, Maureen McMahon, Joseph Mears, Raji Menon, Nghia Millard, Pavel Morozov, Aparna Nathan, Fernanda Payan‐Schober, Michael Peters, Michelle Petri, Chaim Putterman, Deepak A. Rao, Soumya Raychaudhuri, Bill Robinson, Saori Sakaue, Hemant Suryawanshi, Thomas Tuschl, P.J. Utz, Kathryn Weinand, Michael Weisman, David Wofsy, Steve Woodle, Qian Xiao, 张璠 Zhang Fan, Ya-Chi Ho, Joseph Craft
Although loss of B cell tolerance, autoantibody production, and immune complex deposition are hallmarks of systemic lupus erythematosus (SLE), CD8 + T cell infiltration in the kidneys is the best predictor of poor prognosis in lupus nephritis, a severe manifestation of SLE. Here, we examined the origin, differentiation, and functional consequences of CD8 + T cells infiltrating kidneys in lupus-prone mice. TCF-1 + stem-like CD8 + T cells in renal-draining lymph nodes underwent T cell receptor (TCR)-dependent, antigen-driven expansion with differentiation into cytotoxic kidney-infiltrating cells that promoted tissue injury contingent on CD4 + T cell help and interleukin (IL)-21 and IL-15 signaling. CD8 + T cell differentiation was marked by persistent AP-1 activity and cytotoxic function despite increased expression of immune checkpoints. A parallel program of CD8 + T cell differentiation in the kidneys of patients with lupus nephritis reflected shared pathogenesis. Thus, a T cell differentiation program analogous to that in chronic infections and cancer is found in lupus; however, CD8 + T cells in systemic autoimmunity retain effector function despite terminal differentiation.