Uncontrolled T helper type 1 (TH1) and TH17 cells are associated with autoimmune responses. We identify surface lymphotoxin-α (LT-α) as common to TH0, TH1 and TH17 cells and employ a unique strategy to target these subsets using a depleting monoclonal antibody (mAb) directed to surface LT-α. Depleting LT-α–specific mAb inhibited T cell–mediated models of delayed-type hypersensitivity and experimental autoimmune encephalomyelitis. In collagen-induced arthritis (CIA), preventive and therapeutic administration of LT-α–specific mAb inhibited disease, and immunoablated T cells expressing interleukin-17 (IL-17), interferon-γ and tumor necrosis factor-α (TNF-α), whereas decoy lymphotoxin-β receptor (LT-βR) fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of Fcγ receptor binding and antibody-dependent cellular cytotoxicity activity, abolished all in vivo effects. Efficacy in CIA was preceded by a loss of rheumatoid-associated cytokines IL-6, IL-1β and TNF-α within joints. These data indicate that depleting LT-α–expressing lymphocytes with LT-α–specific mAb may be beneficial in the treatment of autoimmune disease.

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We thank H. Nguyen, M. Zhou and the Translational Immunology group for animal studies; A. Gurney; B. Kearce, M.-H. Xie, C. Adams, K. McCutcheon and Antibody Engineering Department for antibody support; C. Austin for pathology support; N. Crellin and A. Iyer for FACS support; and W. Ouyang, F. Martin and H. Spits for manuscript critique.

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Author notes

    • Eugene Y Chiang
    •  & Ganesh A Kolumam

    These authors contributed equally to this work.


  1. Departments of Immunology, South San Francisco, California, USA.

    • Eugene Y Chiang
    • , Ganesh A Kolumam
    • , Xin Yu
    • , Michelle Francesco
    • , Sinisa Ivelja
    • , Ivan Peng
    • , Peter Gribling
    • , Jean Shu
    • , Wyne P Lee
    • , Canio J Refino
    • , Mercedesz Balazs
    • , Andres Paler-Martinez
    • , Devavani Chatterjea
    •  & Jane L Grogan
  2. Assay and Automation Technology, South San Francisco, California, USA.

    • Allen Nguyen
    •  & Judy Young
  3. Tumor Biology and Angiogenesis, South San Francisco, California, USA.

    • Kai H Barck
    •  & Richard A D Carano
  4. Pathology, Genentech, Inc., South San Francisco, California, USA.

    • Ron Ferrando
    •  & Lauri Diehl


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E.Y.C. performed in vitro assays and analyzed in vivo study end points. G.A.K. developed MBP-TCR–transgenic T cell transfer experiments. D.C., M.F. and X.Y. contributed to screening and characterization of mAbs, in vitro assays and paw joint ELISA. A.P.-M. performed Luminex assays. P.G., J.S. and W.P.L. performed collagen-induced arthritis studies. J.Y. and A.N. performed competition assays and established mouse LT-α3 ELISA. S.I., I.P. and C.J.R. performed delayed hypersensitivity and T cell transfer studies. M.B. supervised in vivo studies. L.D. and R.F. performed histology and immunohistochemistry. R.A.D.C. and K.H.B. performed micro-computed tomographic imaging and analysis. J.L.G. supervised the project and drafted manuscript.

Competing interests

All authors work for Genentech, which develops and markets drugs for a profit.

Corresponding author

Correspondence to Jane L Grogan.

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