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

Zheng-Qi Wu,^1, 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. Snapper^1*

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⁺ TCRß⁺ 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.

Editor: J. N. Weiser

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

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