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Fas Expression on Antigen-Specific T Cells Has Costimulatory, Helper, and Down-Regulatory Functions In Vivo for Cytotoxic T Cell Responses but Not for T Cell-Dependent B Cell Responses¹

Irina Puliaeva^*, Roman Puliaev^*, Andrei Shustov, Mark Haas and Charles S. Via^2,*,

^* Department of Pathology, Uniformed Services University of Health Sciences, Bethesda, MD 20814; Department of Medicine, Rheumatology Division, University of Maryland School of Medicine, Baltimore, MD 21201; and Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287

Fas-mediated apoptosis is an important contributor to contraction of Ag-driven T cell responses acting only on activated Ag-specific T cells. The effects of targeted Fas deletion on selected cell populations are well described however little is known regarding the consequences of Fas deletion on only activated Ag-specific T cells. We addressed this question using the parent-into-F₁ (PF₁) model of acute or chronic (lupus-like) graft-vs-host disease (GVHD) as a model of either a CTL-mediated or T-dependent B cell-mediated response, respectively. By transferring Fas-deficient lpr donor T cells into Fas-intact F₁ hosts, the in vivo role of Ag-specific T cell Fas can be determined. Our results demonstrate a novel dichotomy of Ag-specific T cell Fas function in that: 1) Fas expression on Ag-activated T cells has costimulatory, helper, and down-regulatory roles in vivo and 2) these roles were observed only in a CTL response (acute GVHD) and not in a T-dependent B cell response (chronic GVHD). Specifically, CD4 T cell Fas expression is important for optimal CD4 initial expansion and absolutely required for help for CD8 effector CTL. Donor CD8 T cell Fas expression played an important but not exclusive role in apoptosis and down-regulation. By contrast, CD4 Fas expression played no detectable role in modulating chronic GVHD induction or disease expression. These results demonstrate a novel role for Ag-specific T cell Fas expression in in vivo CTL responses and support a review of the paradigm by which Fas deficiency accelerates lupus in MRL/lpr lupus-prone mice.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These studies were supported by National Institutes of Health Grant AI 47466 (to C.S.V.). R.P. and A.S. are recipients of an Engelicheff Fellowship Award from the Maryland Chapter of the Arthritis Foundation.

² Address correspondence and reprint requests to Dr. Charles S. Via, Department of Pathology, Uniformed Services University of Health Sciences, Room B3-100, 4301 Jones Bridge Road, Bethesda, MD 20814. E-mail address: cvia{at}usuhs.mil

³ Abbreviations used in this paper: AICD, activation-induced cell death; GVHD, graft-vs-host disease; IVCCA, in vivo cytokine capture assay; PF₁, parent-into-F₁; WT, wild type; FasL, Fas ligand.