Evidence for Naturally Acquired T Cell-Mediated Mucosal Immunity to Neisseria meningitidis

Abstract

Naturally acquired protective immunity against Neisseria meningitidis is thought to partially explain the disparity between the high levels of carriage in the human nasopharynx and the rare incidence of disease. To investigate this immunity to Neisseria meningitidis at the mucosal level, in vitro cellular responses to outer membrane vesicle preparations derived from this pathogen were examined using mononuclear cells from the palatine tonsils of adults and children. Characterization of these responses was achieved by depletion of CD45RA+, CD45RO+, and CD19+ populations and outer membrane vesicles derived from isogenic mutants expressing different serosubtypes of the major outer membrane protein, porin A (PorA), no PorA and membrane preparations from a mutant with no LPS (LpxA−). The magnitude of cellular proliferative responses against the outer membrane vesicles were strongly associated with age and were largely T cell mediated, involving both CD45RO+ and CD45RA+ T cell phenotypes. Responses were not dependent on LPS but consisted of both PorA cross-specific and non-PorA-dependent responses. Cellular immunity against Neisseria meningitidis was found to be frequently associated with systemic IgG Abs but was not associated with serum bactericidal Abs. For the first time our results demonstrate an age-associated acquisition of mucosal T effector/memory cell responses to Neisseria meningitidis. This mucosal cellular immunity can be present in the absence of serum bactericidal Abs, a classical marker of protective immunity.

Absence of Mucosal Immunity in the Human Upper Respiratory Tract to the Commensal Bacteria Neisseria lactamica but Not Pathogenic Neisseria meningitidis during the Peak Age of Nasopharyngeal Carriage

“…Although our observations are limited by the use of tonsillar tissue obtained from patients with tonsillar disease, the tonsils were not removed during periods of active inflammation. In addition, immunohistochemical analyses have not revealed marked neutrophil infiltration or areas of necrosis in the excised tissue (16,19), which is immunologically responsive to experimental stimuli. Also, there is no evidence of reduced colonization rates of Neisseria species in individuals requiring tonsillectomies as demonstrated by the high frequency of Nm beneath the mucosal surface of tonsil specimens when examined by immunohistochemistry (23).…”

“…They are naturally produced and are therefore physiologically relevant in vivo (25). In addition, OMV have been used extensively by ourselves (16,19) and others (26,27) …”

“…Asymptomatic carriage primes an adaptive immune response within 2 wk of colonization (13) and is associated with increased titers of salivary IgA (14) and serum IgG (15). We have demonstrated the presence of memory T cell responses to Nm outer membrane vesicles (OMV) in human palatine tonsils (PT) which increase with age (16). However, although colonization by Nm induces a rapid immune response that protects against invasive disease, carriage studies have shown that single strains may colonize for several months before being cleared (17,18).…”

“…CellQuest software (BD Biosciences) was used for data acquisition and the data were analyzed using FlowJo software (Tree Star). Phenotypic acquisition was performed as previously described (16).…”

“…TMNC were isolated from PT using a previously described method (16) and resuspended in complete cell culture medium (RPMI 1640; Invitrogen) supplemented with 4 mM L-glutamine, 100 U/ml penicillin, 0.1 mg/ml streptomycin, 20 mM HEPES (all from Sigma-Aldrich), and either 10% (v/v) FCS (Harlan Laboratories) or 1% (v/v) heat-inactivated human AB serum (National Blood Service) as indicated.…”