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.

In this population, T cell-mediated immunological memory potentially capable of pathogen clearance and immune surveillance is common but is not associated with the absolute interruption of pneumococcal carriage. How this naturally acquired immune memory influences pneumococcal vaccine efficacy remains to be determined.

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The normal flora that colonizes the mucosal epithelia has evolved diverse strategies to evade, modulate, or suppress the immune system and avoid clearance. Neisseria lactamica and Neisseria meningitidis are closely related obligate inhabitants of the human upper respiratory tract. N. lactamica is a commensal but N. meningitidis is an opportunistic pathogen that occasionally causes invasive disease such as meningitis and septicemia. We demonstrate that unlike N. meningitidis, N. lactamica does not prime the development of mucosal T or B cell memory during the peak period of colonization. This cannot be explained by the induction of peripheral tolerance or regulatory CD4+CD25+ T cell activity. Instead, N. lactamica mediates a B cell-dependent mitogenic proliferative response that is absent to N. meningitidis. This mitogenic response is associated with the production of T cell-independent polyclonal IgM that we propose functions by shielding colonizing N. lactamica from the adaptive immune system, maintaining immunological ignorance in the host. We conclude that, in contrast to N. meningitidis, N. lactamica maintains a commensal relationship with the host in the absence of an adaptive immune response. This may prolong the period of susceptibility to colonization by both pathogenic and nonpathogenic Neisseria species.

We sought to determine whether palatine tonsils (PTs) harbor naturally acquired influenza-specific T cell immunity and whether routine parenteral immunization with influenza vaccine influences mucosal and systemic T cell reactivity. We demonstrate that tonsillar and peripheral blood mononuclear cells (PBMCs) proliferate strongly to influenza antigens, suggesting that naturally acquired immunity exists within both the mucosal and systemic compartments. Influenza vaccination induced significantly stronger T cell responses in both PTs and blood, in addition to increasing titers of anti-influenza antibodies in serum and saliva. More-rapid proliferative responses of PTs after vaccination were associated with a shift from a response involving both CD45RA+ and CD45RO+ T cells to an entirely CD45RO+-dependent response. Interestingly, the ratio of interferon- gamma to interleukin-5 was dramatically higher in cultures of PT T cells responding to influenza than in PBMCs. Our data indicate that parenteral influenza vaccination influences both mucosal and systemic naturally acquired T cell immunity.

Asymptomatic carriage of Neisseria meningitidis is common (5-35% of individuals) while the incidence of invasive meningococcal disease is fairly low (<1-5 per 100,000 per annum in Europe). Naturally acquired protective immunity may account for this difference. In this study, we investigated the relationship between anti-meningococcal salivary IgA and age and carriage. We showed that salivary IgA to a range of meningococcal antigens increased successively with age with some specificity for commonly circulating serosubtypes. In a group of 258 students 37 (14%) of whom were carriers of N. meningitidis serogroup B, higher levels of specific IgA were associated with carriage. Stratified analysis revealed a positive relationship between smoking and specific anti- N. meningitidis IgA independent of current carriage, weighted odds ratio (OR) 4.1 (95% CI 1.1-18) and OR 3.8 (95% CI 0.96-16) for reference strains B:1:P1.14 and B:4:P1.5,4 respectively. These data implicate IgA as a factor in host defence from meningococcal invasion, although the precise mechanisms remain uncertain.

Parenteral MenB vaccination selectively reprograms preexisting naturally acquired mucosal immunity. As new-generation protein-based MenB vaccine candidates undergo evaluation, the impact of these vaccines on mucosal immunity in both adults and children will need to be addressed.

The importance of T cells in the generation of antigen-specific B-cell immunity has been extensively described, but the role B cells play in shaping T-cell memory is uncertain. In healthy controls, exposure to Neisseria meningitidis in the upper respiratory tract is associated with the generation of memory T cells in the mucosal and systemic compartments. However, we demonstrate that in B celldeficient subjects with X-linked agammaglobulinemia (XLA), naturally acquired Tcell memory responses to meningococcal antigens are reduced compared with healthy control patients. This difference is not found in T-cell memory to an obligate respiratory pathogen, influenza virus. Accordingly, we show that meningococcal antigens up-regulate major histocompatibility complex ( IntroductionThe role of T cells in the generation and shaping of antigen-specific B-cell responses has been extensively researched. It is well established that cognate interactions between T and B cells induces germinal center formation, isotype switching, and affinity maturation. In addition, it is clear that reciprocal signaling from the B cell to the T cell through MHC-T-cell receptor (TCR) interactions, as well as following interactions between costimulatory receptors and CD40-CD40L binding, also influence the activation of the T cell. Although antigen presentation by B cells only weakly primes naive T cells, robust recall T-cell responses are effectively stimulated in vivo. 1,2 However, the effects of these events on the development and maintenance of T-cell memory and their importance in the generation of immunity to infection in humans are unclear.Neisseria meningitidis (Nm), a frequent colonizer of the upper respiratory tract (URT), is a leading cause of meningitis and septicemia in children and adolescents. 3,4 Although Nm carriage occurs in 10% to 40% of the population in industrialized countries, 3,5 invasive disease is infrequent. We and others have described the generation of naturally acquired T-and B-cell immunity to the meningococcus with age both in the systemic and mucosal compartments. [6][7][8][9] Effector T cells provide help to B cells, resulting in the generation of circulating anti-Nm complementfixing antibodies that are associated with protection from invasive disease. 10 Deficiencies of B cells and loss of splenic function are associated with increased susceptibility to meningococcal disease. Patients who have undergone myeloablation before bone marrow transplantation or who have received anti-B-cell monoclonal antibodies therapeutically are at increased risk of infection by capsulated bacteria. 11 We speculate that these susceptibilities are not simply attributable to an impairment of B-cell effector function. B cells are abundant in URT lymphoid tissue, 6 and we have therefore investigated the possibility that B-cell interactions with CD4 T cells in the mucosal compartment are key to the development and maintenance of anti-Nm T-cell memory both at the mucosal surface and in the circulation.A variety of B cell-deficient animal m...