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Infection and Immunity, January 2003, p. 196-204, Vol. 71, No. 1
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.1.196-204.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

4-1BB (CD137) Differentially Regulates Murine In Vivo Protein- and Polysaccharide-Specific Immunoglobulin Isotype Responses to Streptococcus pneumoniae

Zheng-Qi Wu,1,{dagger} Abdul Q. Khan,1 Yi Shen,1 Karen M. Wolcott,2 Wojciech Dawicki,3 Tania H. Watts,3 Robert S. Mittler,4 and Clifford M. Snapper1*

Department of Pathology,1 Biomedical Instrumentation Center, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814,2 Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S1A8,3 The Yerkes Regional Primate Research Center, Atlanta Georgia 303294

Received 6 August 2002/ Returned for modification 23 September 2002/ Accepted 23 October 2002

4-1BB (CD137) is induced on activated CD4+ and CD8+ T cells and delivers a costimulatory signal upon binding the 4-1BB ligand (4-1BBL) expressed on antigen-presenting cells. Induction of 4-1BB is dependent on activation via the T-cell receptor (TCR) and possibly CD28. It was previously demonstrated that both an in vivo protein (pneumococcal surface protein A [PspA])- and polysaccharide (phosphorylcholine [PC] determinant of teichoic acid)-specific immunoglobulin (Ig) isotype response to Streptococcus pneumoniae was dependent on CD4+ TCR{alpha}ß+ T cells and B7-dependent costimulation through CD28. We thus postulated that 4-1BB costimulation would also play a role in regulating the in vivo anti-PspA and anti-PC response to S. pneumoniae. We demonstrate that mice genetically deficient in 4-1BBL elicit a markedly reduced IgM and IgG anti-PC but normal primary and secondary IgG anti-PspA responses to S. pneumoniae relative to those for wild-type mice. However, injection of an agonistic anti-4-1BB monoclonal antibody (MAb), while having no significant effect on the anti-PC response, strongly inhibits the primary anti-PspA response, the generation of PspA-specific memory, and germinal center formation but does not induce a lasting state of tolerance. In contrast, anti-4-1BB MAb has no effect on the anti-PspA response when injected only at the time of secondary immunization. Delay of the addition of anti-4-1BB leads to progressively less inhibition of the primary response up to day 8. This inhibition is independent of CD8+ T cells and is associated with the expansion of CD4+ T cells with an activated phenotype, which is partly dependent on B7-dependent costimulation. These data are the first to suggest a stimulatory role for endogenous 4-1BB-4-1BBL interactions during a humoral immune response to a pathogen and further underscore significant differences in costimulation requirements for an in vivo protein- versus polysaccharide-specific Ig isotype response to an extracellular bacterium.

* Corresponding author: Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814. Phone: (301) 295-3490. Fax: (301) 295-1640. E-mail: csnapper{at}usuhs.mil.

Editor: J. N. Weiser

{dagger} Present address: Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892.

Infection and Immunity, January 2003, p. 196-204, Vol. 71, No. 1
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.1.196-204.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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