S160 Abstracts

partial DiGeorge syndrome is severely disturbed starting atinfancy and may be more skewed in patients with upperrespiratory infections than in those without infections.

doi:10.1016/j.clim.2009.03.471

S.99. T-bet Controls Regulatory T Cell FunctionDuring type-1 InflammationDaniel Campbell1, Meghan Koch2, Kevin Urdahl2. 1BenaroyaResearch Institute, Seattle, WA; 2University of Washington,Seattle, WA

Several subsets of Foxp3+regulatory T cells (TR) work inconcert to maintain normal immune homeostasis in second-ary lymphoid tissues and at peripheral sites of infection andinflammation. However, the molecular basis underlying TRphenotypic and functional diversity remain obscure. We showthat during strong TH1 responses, Foxp3+TR upregulate theTH1-specifying transcription factor Tbx21 (T-bet). T-betcontrols TR expression of the TH1-associated chemokinereceptor CXCR3, and T-bet+TR accumulate at sites of TH1-mediated inflammation in mice during persistent infectionwith Mycobacterium tuberculosis (Mtb). Furthermore, T-betexpression by TR is required for their normal homeostasis andfunction during strong TH1-driven immune responses in vivo.Thus, our data demonstrate that within a subset of CD4+Tcells, the activities of Foxp3 and T-bet are overlaid, resultingin functional TR capable of expanding during type-1inflammation and suppressing TH1 responses in vivo.

doi:10.1016/j.clim.2009.03.472

S.100. SAPAugments Proximal T Cell Receptor SignalStrength Necessary for Restimulation-inducedApoptosis of Activated T CellsAndrew Snow1, Rebecca Marsh2, Scott Krummey1, PhilipRoehrs2, Kejian Zhang2, Lisa Filipovich2, Helen Su1, JacobBleesing2, Michael Lenardo1. 1NIAID, National Institutes ofHealth, Bethesda, MD; 2Cincinnati Children's HospitalMedical Center, Cincinnati, OH

Loss of SLAM-associated protein (SAP) molecularly definesmost cases of X-linked lymphoproliferative disease (XLP).Although XLP is generally considered a primary immunode-ficiency, SAP deficiency is also associated with bouts of B andTcell hyperproliferation often linked to infection, suggestingXLP also encompasses impaired lymphocyte homeostasis. Werecently studied several XLP patients with a history of B celllymphoma and/or hyperactive T cell-driven disease akin tohemophagocytic lymphohistiocytosis (HLH). Strikingly, wefound that activated XLP patient T cells were resistant toapoptosis induced by T cell receptor (TCR) restimulation, anautoregulatory form of cell death that constrains T cellexpansion during the immune response. Silencing SAPexpression in normal donor T cells recapitulated this defect,indicating SAP is required for a specific TCR-inducedapoptotic signal. Genomic and biochemical analysis revealedthat loss of SAP results in impaired upregulation of key pro-

apoptotic molecules following TCR restimulation, includingFASL and BIM. However, FASL/BIM induction and apoptosiswas rescued in XLP T cells by extensive CD3 crosslinking orPMA/ionomycin treatment, suggesting SAP potentiates prox-imal TCR signal strength required for apoptosis execution.Furthermore, we demonstrated that SLAM family receptorNTB-A participates in transducing this signal, ostensiblythrough increased SAP association concomitant with displa-cement of the protein tyrosine phosphatase SHP-1 after TCRre-engagement. In summation, our work sheds new light onthe propensity for lymphoproliferative disease in XLP due todefective TCR-induced death. We propose this defect isparticularly relevant to the unbridled CD8+T cell expansioncharacteristic of EBV-associated fulminant infectious mono-nucleosis in XLP patients.

doi:10.1016/j.clim.2009.03.473

S.101. TNFa Blockade Exacerbates Disease in aPsoriasis-like Skin Inflammation Model ThroughEnhancing Th17 Cell Function while SuppressingCD4+Foxp3+T Cell ExpansionHakling 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 proin-flammatory and co-stimulatory effects on a broad range of celltypes, thus playing a major role in orchestrating inflammationand immunity. TNFa antagonists including soluble anti-TNFmonoclonal antibodies Infliximab® and Adalimumab® as wellas soluble TNF receptor (sTNFRIIFc) Etanercept® have demon-strated clinical efficacy in treating human rheumatoid arthritis(RA), ankylosing spondylitis, psoriatic arthritis and Crohn'sdisease. However, one unexpected side effect of TNFantagonism reported in the literature is the new onset orworsening of psoriatic skin lesions. It is paradoxical that TNFaantagonists are efficacious in treating psoriasis in somepatients, while induceing psoriasis in a subset other patients.We have developed a skin inflammation model by adoptivetransfer of CD4+CD45RBhiCD25-naïve T cells into scid/scidrecipient mice. Certain histological and immuno-pathologicalfeatures in thismodelmimic those of humanpsoriasis. Herewecompared the effects of either IL12/23p40 or TNFa pathwayblockade in our model of skin inflammation. We found thatconsistent with our previous report, antagonizing the IL12/23p40p40 pathway almost completely ameliorated skininflammation. Strikingly, neutralization of TNFa with a solublemurineTNFRIIFc chimeric protein exacerbated skin inflamma-tion. We further demonstrated that TNFa neutralizationenhanced Th17 cell activity through up-regulation of IL-21,concomitant with a decrease in the percentage of Tregpopulation found in the draining lymph node. Our studyhighlights the protective role of TNFa in the immune systemthat should be taken into consideration before treatingpatients with anti-TNFa agents.

doi:10.1016/j.clim.2009.03.474