Peroxisome proliferator-activated receptor gamma is required for CD4+ T cell-mediated lymphopenia-associated autoimmunity

WJ Housley, CO Adams, AG Vang, S Brocke, FC Nichols, M LaCombe, TV Rajan, RB Clark

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

The nuclear hormone receptor peroxisome proliferator-activated receptor g (PPARg) was shown to play an immunoregulatory
role in many immune-related cell types, and activation of PPARg was reported to be an effective therapeutic approach in murine
and human autoimmune disease. However, despite an association between lymphopenia and autoimmunity, there has been no
study on the role of T cell PPARg in lymphopenia-associated autoimmunity. In the present studies, we examined the role of
PPARg in CD4+ T cells in two murine models of lymphopenia-associated autoimmunity. Surprisingly, we found that PPARg
expression in CD4+ CD252 T cells (T effector cells [Teffs]) is actually required for development of autoimmunity under lymphopenic conditions. Mechanistically, the inability of PPARg-deficient (T-PPAR) Teffs to mediate lymphopenic autoimmunity is
associated with a significant decrease in accumulation of Teffs in the spleen, lymph nodes, and tissues after adoptive transfer.
This abnormal accumulation of T-PPAR Teffs was associated with defects in both in vivo proliferation and survival. Additionally,
T-PPAR Teffs demonstrated decreased cytokine production in inflammatory sites and decreased expression of the homing receptor
a4b7. Finally, these abnormalities in T-PPAR Teff function were not elicited by lymphopenia alone but also required the
additional activation involved in the mediation of autoimmunity. Thus, in contrast to its documented immunosuppressive role,
we identified an unexpected function for PPARg in Teffs: a role in Teff proliferation and survival in lymphopenia-associated
autoimmunity. These findings highlight both the multifunctional role of PPARg in T cells and the complexity of PPARg as a
potential therapeutic target in autoimmunity.
Original languageEnglish
Pages (from-to)4161–4169
Number of pages10
JournalJournal of immunology (Baltimore, Md. : 1950)
Volume187
Issue number8
DOIs
Publication statusPublished - Sept 2011

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