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. 2008 Jun;76(6):2678-84.
doi: 10.1128/IAI.00141-08. Epub 2008 Apr 7.

Protection against nasopharyngeal colonization by Streptococcus pneumoniae is mediated by antigen-specific CD4+ T cells

Krzysztof Trzciński  1 , Claudette M Thompson, Amit Srivastava, Alan Basset, Richard Malley, Marc Lipsitch
Affiliations

Protection against nasopharyngeal colonization by Streptococcus pneumoniae is mediated by antigen-specific CD4+ T cells

Krzysztof Trzciński et al. Infect Immun. 2008 Jun.

Abstract

CD4(+) T-cell-dependent acquired immunity confers antibody-independent protection against pneumococcal colonization. Since this mechanism is poorly understood for extracellular bacteria, we assessed the antigen specificity of the induction and recall of this immune response by using BALB/c DO11.10Rag(-/-) mice, which lack mature B and T cells except for CD4(+) T cells specific for the OVA(323-339) peptide derived from ovalbumin. Serotype 6B Streptococcus pneumoniae strain 603S and unencapsulated strain Rx1Delta lytA were modified to express OVA(323-339) as a fusion protein with surface protein A (PspA) (strains 603OVA(1) and Rx1Delta lytAOVA(1)) or with PspA, neuraminidase A, and pneumolysin (Rx1Delta lytAOVA(3)). Whole-cell vaccines (WCV) were made of ethanol-killed cells of Rx1Delta lytA plus cholera toxin (CT) adjuvant, of Rx1Delta lytAOVA(1) + CT (WCV-OVA(1)), and of Rx1Delta lytAOVA(3) + CT (WCV-OVA(3)). Mice intranasally immunized with WCV-OVA(1), but not with WCV or CT alone, were protected against intranasal challenge with 603OVA(1). There was no protection against strain 603S in mice immunized with WCV-OVA(1). These results indicate antigen specificity of both immune induction and the recall response. Effector action was not restricted to antigen-bearing bacteria since colonization by 603S was reduced in animals immunized with vaccines made of OVA-expressing strains when ovalbumin or killed Rx1Delta lytAOVA(3) antigen was administered around the time of challenge. CD4(+) T-cell-mediated protection against pneumococcal colonization can be induced in an antigen-specific fashion and requires specific antigen for effective bacterial clearance, but this activity may extend beyond antigen-expressing bacteria. These results are consistent with the recruitment and/or activation of phagocytic or other nonspecific effectors by antigen-specific CD4(+) T cells.

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Figures

FIG. 1.
FIG. 1.
Intranasal colonization of immunocompetent mice with S. pneumoniae strain 603 (A) and its streptomycin-resistant mutant 603S (B) after immunization with WCVs. (A) Comparison of the colonization density of C57BL/6J mice immunized with various doses of WCV made of Rx1ΔlytA strain (0.01, 1, or 100 μg) or CT alone (0). (B) Protection of BALB/c mice after immunization with WCV-OVA1 vaccine made of Rx1ΔlytAOVA1 strain in comparison with mice immunized with CT alone. Solid lines indicate group medians. P values refer to results of the Mann-Whitney test for differences in the distribution of CFU per nasal wash between groups.
FIG. 2.
FIG. 2.
Comparison of the density of intranasal colonization by S. pneumoniae strains 603OVA1 and 603S in DO11.10 RAG−/− mice after immunization with CT alone (CT), WCV made of the Rx1ΔlytA strain (WCV), or WCV made of Rx1ΔlytAOVA1 (WCV-OVA1) as indicated below the x axis. The number of animals in each group is depicted at the bottom. Solid lines indicate group medians. P values refer to results of the Mann-Whitney test for differences in the distribution of CFU per nasal wash between groups.
FIG. 3.
FIG. 3.
Comparison of the density of intranasal colonization with S. pneumoniae strain 603S in DO11.10 RAG−/− mice immunized either with CT alone (CT), WCV made of Rx1ΔlytAOVA1 (WCV-OVA1), or WCV made of Rx1ΔlytAOVA3 (WCV-OVA3) as indicated below the x axis and stimulated during colonization intranasally with either ovalbumin, killed cells of Rx1ΔlytA (WCA), or killed cells of Rx1ΔlytAOVA3 (WCA-OVA3) for 4 days after challenge with 603S. The number of animals in each group is depicted at the bottom. Solid lines indicate group medians. P values refer to results of the Mann-Whitney test for differences in the distribution of CFU per nasal wash between groups.
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