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Journal of Virology, April 2002, p. 3943-3951, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3943-3951.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Role of Lymphotoxin {alpha} in T-Cell Responses during an Acute Viral Infection

M. Suresh,1,{dagger} Gibson Lanier,1 Mary Katherine Large,1 Jason K. Whitmire,1 John D. Altman,1 Nancy H. Ruddle,2 and Rafi Ahmed1*

Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322,1 Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 065202

Received 1 November 2001/ Accepted 10 January 2002

The importance of lymphotoxin {alpha} (LT{alpha}) in lymphoid organogenesis is well established. Although LT{alpha} has been implicated in the pathogenesis of T-cell-mediated immunopathologies, the requirement for LT{alpha} in T-cell activation and effector function in vivo is not well understood. To determine the role of LT{alpha} in T-cell activation in vivo, we compared the generation of antigen-specific T-cell responses between wild type (+/+) and LT{alpha}-deficient (LT{alpha}-/-) mice during an acute infection with lymphocytic choriomeningitis virus (LCMV). Our studies showed that LCMV-infected LT{alpha}-/- mice had a profound impairment in the activation and expansion of virus-specific CD8 T cells in the spleen, as determined by cytotoxicity assays, intracellular staining for gamma interferon, and staining with major histocompatibility complex class I tetramers. Further, the nonlymphoid organs of LT{alpha}-/- mice also contained substantially lower number of LCMV-specific CD8 T cells than those of +/+ mice. Greatly reduced virus-specific CD8 T-cell responses in LT{alpha}-/- mice led to a defect in LCMV clearance from the tissues. In comparison to that in +/+ mice, the activation of LCMV-specific CD4 T cells was also significantly attenuated in LT{alpha}-/- mice. Adoptive transfer experiments were conducted to determine if abnormal lymphoid architecture in LT{alpha}-/- mice caused the impairment in the activation of LCMV-specific T-cell responses. Upon adoptive transfer into +/+ mice, the activation and expansion of LCMV-specific LT{alpha}-/- T cells were restored to levels comparable to those of +/+ T cells. In a reciprocal cell transfer experiment, activation of +/+ T cells was significantly reduced upon transfer into LT{alpha}-/- mice. These results showed that impairment in the activation of LCMV-specific T cells in LT{alpha}-/- mice may be due to abnormal lymphoid architecture and not to an intrinsic defect in LT{alpha}-/- T cells.

* Corresponding author. Mailing address: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, G211 Rollins Research Center, 1510 Clifton Rd., Atlanta, GA 30322. Phone: (404) 727-3571. Fax: (404) 727 3722. E-mail: ra{at}microbio.emory.edu.

{dagger} Present address: Department of Pathobiological Sciences, University of Wisconsin—Madison, Madison, WI 53706.

Journal of Virology, April 2002, p. 3943-3951, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3943-3951.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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