CD4⁺T cells mediate antibody-independent acquired immunity to pneumococcal colonization

Abstract

Acquired immunity to Streptococcus pneumoniae (pneumococcus) has long been assumed to depend on the presence of anticapsular antibodies. We found, however, that colonization with live pneumococci of serotypes 6B, 7F, or 14 protected mice against recolonization by any of the serotypes and that protection from acquisition of a heterologous or homologous strain did not depend on anticapsular antibody. Further, intranasal immunization by live pneumococcal colonization or by a killed, nonencapsulated wholecell vaccine protected antibody-deficient mice against colonization, suggesting independence of antibodies to any pneumococcal antigens. Protection by intranasal immunization with whole-cell vaccine was completely abrogated in T cell-deficient mice, and in mice that were congenitally deficient in CD4 ؉ T cells or depleted of these cells at the time of challenge. In contrast, mice congenitally deficient in, or depleted of, CD8 ؉ T cells were fully protected. Protection in this model was observed beyond 2 months after immunization, arguing against innate or nonspecific immune mechanisms. Thus, we find that immunity to pneumococcal colonization can be induced in the absence of antibody, independent of the capsular type, and this protection requires the presence of CD4 ؉ T cells at the time of challenge.Streptococcus pneumoniae ͉ cell-mediated immunity ͉ vaccine A lmost 1 million children in the developing world die of infections due to Streptococcus pneumoniae (pneumococcus) each year (1). Pneumococcus is considered an ''extracellular'' bacterial pathogen, i.e., it is killed upon ingestion by phagocytic cells. Ingestion is facilitated by antibody (Ab) to its capsular polysaccharides (PS), of which there are at least 90 different serotypes. The two existing pneumococcal vaccines are based on injected mixtures of PS. Plain (unconjugated) PS vaccine contains 23 serotypes but is not efficacious in children Ͻ2 years old and therefore fails to protect those at highest risk. Protein-conjugated PS contains seven serotypes and protects infants (2), but it is difficult to manufacture (resulting in repeated shortages), is expensive, needs refrigeration, requires multiple injections, and does not include many of the capsular serotypes that cause pneumococcal disease in the developing world. Furthermore, serotype replacement, whereby pneumococcal serotypes not included in the conjugate vaccine become more prevalent causes of colonization and disease, has already been observed in clinical trials (3) and in epidemiologic studies (4) after implementation of conjugate vaccine immunization programs. Therefore, despite the success of the capsule-based vaccines, alternative strategies are urgently needed.The success of serum therapy (passive transfer of anticapsular Ab from hyperimmune animals) and the efficacy of PS and PS-protein conjugate vaccines have clearly demonstrated that anticapsular Ab alone is sufficient to treat or prevent pneumococcal disease. Furthermore, studies in animals (5) and humans (6) clearly demonstrate that antica...

B cell mediated priming following pneumococcal colonization

“…The production of anti-PPS IgG antibody following pneumococcal colonization in mice has been demonstrated previously and confirmed in our model [13]. Moreover, work by Malley et al and van Rossum et al has shown that murine colonization stimulates the production of CD4 + T cells [23,5]. Collectively they demonstrated that mice lacking these cells remained persistently colonized, similar to severe-combined immunodeficient mice.…”

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

“…vaccination with WCA were presaged by studies of pneumococci in naïve mice: the cellular response to pneumococcal infection had suggested a role of CD4+ T cells in the control of pneumonia and blood-borne infections (54), and the gradual clearance after intranasal challenge was similar in μMT −/− and normal animals (55). The observation that (human) children naturally increase their immunity to pneumococci of many serotypes simultaneously and before detectable capsular antibodies arise prompted our suggestion that an antibody-independent, CD4+ T cell-dependent process is an early contributor to natural pneumococcal immunity (53,56).…”

“…Although plasma antibody responses were induced in normal mice, the clearance unexpectedly was inducible in μMT −/− mice (53), which congenitally lack antibody responses. Furthermore, this immunization failed in nude mice (lacking T lymphocytes) and MHC II-deficient mice (lacking CD4+ T cell responses), but it worked normally in MHC I-deficient mice (lacking CD8+ T cell responses) (53). The antibody independence and T cell dependence were surprising, because pneumococci are considered extracellular pathogens (killed when phagocytosed) in contrast to microbes such as mycobacteria that can persist within phagocytes and require activated T cells for clearance (28).…”

Clearance of Staphylococcus aureus Nasal Carriage Is T Cell Dependent and Mediated through Interleukin-17A Expression and Neutrophil Influx

“…Our data emulate those obtained in experiments involving Streptococcus pneumoniae nasal colonization. CD4 ϩ T cells were required for immunity against pneumococcal carriage in a murine model, and this occurred in an antibody-independent fashion (20). Another S. pneumoniae study discovered the importance of Th17 responses for clearance.…”