NF-κB–inducing kinase plays an essential T cell–intrinsic role in graft-versus-host disease and lethal autoimmunity in mice
Susan E. Murray, Fanny Polesso, Alexander M. Rowe, Soumen Basak, Yoshinobu Koguchi, Katelynne Gardner Toren, Alexander Hoffmann, David C. Parker
Susan E. Murray, Fanny Polesso, Alexander M. Rowe, Soumen Basak, Yoshinobu Koguchi, Katelynne Gardner Toren, Alexander Hoffmann, David C. Parker
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Research Article Immunology

NF-κB–inducing kinase plays an essential T cell–intrinsic role in graft-versus-host disease and lethal autoimmunity in mice

Abstract

NF-κB–inducing kinase (NIK) is an essential upstream kinase in noncanonical NF-κB signaling. NIK-dependent NF-κB activation downstream of several TNF receptor family members mediates lymphoid organ development and B cell homeostasis. Peripheral T cell populations are normal in the absence of NIK, but the role of NIK during in vivo T cell responses to antigen has been obscured by other developmental defects in NIK-deficient mice. Here, we have identified a T cell–intrinsic requirement for NIK in graft-versus-host disease (GVHD), wherein NIK-deficient mouse T cells transferred into MHC class II mismatched recipients failed to cause GVHD. Although NIK was not necessary for antigen receptor signaling, it was absolutely required for costimulation through the TNF receptor family member OX40 (also known as CD134). When we conditionally overexpressed NIK in T cells, mice suffered rapid and fatal autoimmunity characterized by hyperactive effector T cells and poorly suppressive Foxp3+ Tregs. Together, these data illuminate a critical T cell–intrinsic role for NIK during immune responses and suggest that its tight regulation is critical for avoiding autoimmunity.

Authors

Susan E. Murray, Fanny Polesso, Alexander M. Rowe, Soumen Basak, Yoshinobu Koguchi, Katelynne Gardner Toren, Alexander Hoffmann, David C. Parker

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Figure 8

Acute overexpression of NIK in mature T cells inhibits iTreg suppressive capacity.

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Acute overexpression of NIK in mature T cells inhibits iTreg suppressive...
CD4+ T cells were magnetically purified from NIKtg and littermate WT control spleen and LN, treated with TAT-Cre, and cultured under iTreg-inducing conditions for 3 days. Tregs were then sorted on the basis of CD4, CD25, and GFP, and cultured with CD45.1 naive T cells plus WT APCs and soluble anti-CD3 for an additional 3 days. (A) After iTreg induction and sorting, WT and NIKtg iTregs expressed equivalent Foxp3 and CD25. Plots are gated on live T cells. Numbers reflect percent Foxp3+ T cells. (B) Naive CD45.1 CD4+ T cells were labeled with CellTrace Violet to assess division over the course of 3 days. (C) Data (± SD) are representative of 2 independent experiments.