S.99. T-bet Controls Regulatory T Cell Function During type-1 Inflammation

S160 partial DiGeorge syndrome is severely disturbed starting at infancy and may be more skewed in patients with upper respiratory infections than in those without infections. doi:10.1016/j.clim.2009.03.471

S.99. T-bet Controls Regulatory T Cell Function During type-1 Inflammation Daniel Campbell1, Meghan Koch2, Kevin Urdahl2. 1Benaroya Research Institute, Seattle, WA; 2University of Washington, Seattle, WA Several subsets of Foxp3+regulatory T cells (TR) work in concert to maintain normal immune homeostasis in secondary lymphoid tissues and at peripheral sites of infection and inflammation. However, the molecular basis underlying TR phenotypic and functional diversity remain obscure. We show that during strong TH1 responses, Foxp3+TR upregulate the TH1-specifying transcription factor Tbx21 (T-bet). T-bet controls TR expression of the TH1-associated chemokine receptor CXCR3, and T-bet+TR accumulate at sites of TH1mediated inflammation in mice during persistent infection with Mycobacterium tuberculosis (Mtb). Furthermore, T-bet expression by TR is required for their normal homeostasis and function during strong TH1-driven immune responses in vivo. Thus, our data demonstrate that within a subset of CD4+T cells, the activities of Foxp3 and T-bet are overlaid, resulting in functional TR capable of expanding during type-1 inflammation and suppressing TH1 responses in vivo. doi:10.1016/j.clim.2009.03.472

S.100. SAP Augments Proximal T Cell Receptor Signal Strength Necessary for Restimulation-induced Apoptosis of Activated T Cells Andrew Snow1, Rebecca Marsh2, Scott Krummey1, Philip Roehrs2, Kejian Zhang2, Lisa Filipovich2, Helen Su1, Jacob Bleesing2, Michael Lenardo1. 1NIAID, National Institutes of Health, Bethesda, MD; 2Cincinnati Children's Hospital Medical Center, Cincinnati, OH Loss of SLAM-associated protein (SAP) molecularly defines most cases of X-linked lymphoproliferative disease (XLP). Although XLP is generally considered a primary immunodeficiency, SAP deficiency is also associated with bouts of B and T cell hyperproliferation often linked to infection, suggesting XLP also encompasses impaired lymphocyte homeostasis. We recently studied several XLP patients with a history of B cell lymphoma and/or hyperactive T cell-driven disease akin to hemophagocytic lymphohistiocytosis (HLH). Strikingly, we found that activated XLP patient T cells were resistant to apoptosis induced by T cell receptor (TCR) restimulation, an autoregulatory form of cell death that constrains T cell expansion during the immune response. Silencing SAP expression in normal donor T cells recapitulated this defect, indicating SAP is required for a specific TCR-induced apoptotic signal. Genomic and biochemical analysis revealed that loss of SAP results in impaired upregulation of key pro-

Abstracts apoptotic molecules following TCR restimulation, including FASL and BIM. However, FASL/BIM induction and apoptosis was rescued in XLP T cells by extensive CD3 crosslinking or PMA/ionomycin treatment, suggesting SAP potentiates proximal TCR signal strength required for apoptosis execution. Furthermore, we demonstrated that SLAM family receptor NTB-A participates in transducing this signal, ostensibly through increased SAP association concomitant with displacement of the protein tyrosine phosphatase SHP-1 after TCR re-engagement. In summation, our work sheds new light on the propensity for lymphoproliferative disease in XLP due to defective TCR-induced death. We propose this defect is particularly relevant to the unbridled CD8+T cell expansion characteristic of EBV-associated fulminant infectious mononucleosis in XLP patients. doi:10.1016/j.clim.2009.03.473

S.101. TNFa Blockade Exacerbates Disease in a Psoriasis-like Skin Inflammation Model Through Enhancing Th17 Cell Function while Suppressing CD4+Foxp3+T Cell Expansion Hakling Margery Ma, Lee Napierata, Nancy Stedman, Stephen Benoit, Mary Collins, Cheryl Nickerson-Nutter, Deborah Young. Wyeth Research, Cambridge, MA TNFa is a pleiotropic cytokine that has multiple proinflammatory and co-stimulatory effects on a broad range of cell types, thus playing a major role in orchestrating inflammation and immunity. TNFa antagonists including soluble anti-TNF monoclonal antibodies Infliximab® and Adalimumab® as well as soluble TNF receptor (sTNFRIIFc) Etanercept® have demonstrated clinical efficacy in treating human rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis and Crohn's disease. However, one unexpected side effect of TNF antagonism reported in the literature is the new onset or worsening of psoriatic skin lesions. It is paradoxical that TNFa antagonists are efficacious in treating psoriasis in some patients, while induceing psoriasis in a subset other patients. We have developed a skin inflammation model by adoptive transfer of CD4+CD45RBhiCD25-naïve T cells into scid/scid recipient mice. Certain histological and immuno-pathological features in this model mimic those of human psoriasis. Here we compared the effects of either IL12/23p40 or TNFa pathway blockade in our model of skin inflammation. We found that consistent with our previous report, antagonizing the IL12/ 23p40p40 pathway almost completely ameliorated skin inflammation. Strikingly, neutralization of TNFa with a soluble murineTNFRIIFc chimeric protein exacerbated skin inflammation. We further demonstrated that TNFa neutralization enhanced Th17 cell activity through up-regulation of IL-21, concomitant with a decrease in the percentage of Treg population found in the draining lymph node. Our study highlights the protective role of TNFa in the immune system that should be taken into consideration before treating patients with anti-TNFa agents. doi:10.1016/j.clim.2009.03.474