Initiation of nasopharyngeal-associated lymphoid tissue (NALT) development is independent of the programmed cytokine cascade necessary for the formation of Peyer's patches (PP) and peripheral lymph nodes (PLN), a cytokine cascade which consists of IL-7R, LTalpha1beta2/LTbetaR, and NIK. However, the subsequent organization of NALT seems to be controlled by these cytokine signaling cascades since the maturation of NALT structure is generally incomplete in those cytokine cascade-deficient mice. NALT as well as PP and PLN are completely absent in Id2(-/-) mice. NALT organogenesis is initiated following the adoptive transfer of CD3(-)CD4(+)CD45(+) cells into Id2(-/-) mice, constituting direct evidence that CD3(-)CD4(+)CD45(+) inducer cells can provide an IL-7R-, LTalpha1beta2/LTbetaR-, and NIK-independent tissue organogenesis pathway for secondary lymphoid tissue development.

The class IV semaphorin Sema4A provides a costimulatory signal to T cells. To investigate the possible developmental and regulatory roles of Sema4A in vivo, we generated Sema4A-deficient mice. Although Sema4A-deficient mice develop normally, DCs and T cells from knockout mice display poor allostimulatory activities and T helper cell (Th) differentiation, respectively. Interestingly, in addition to its expression on DCs, Sema4A is upregulated on Th1-differentiating cells, and it is necessary for in vitro Th1 differentiation and T-bet expression. Consequently, in vivo antigen-specific T cell priming and antibody responses against T cell-dependent antigens are impaired in the mutant mice. Additionally, Sema4A-deficient mice exhibit defective Th1 responses. Furthermore, reconstitution studies with antigen-pulsed DCs reveal that DC-derived Sema4A is important for T cell priming, while T cell-derived Sema4A is involved in developing Th1 responses. Collectively, these results indicate a nonredundant role of Sema4A not only in T cell priming, but also in the regulation of Th1/Th2 responses.

Epithelial cells are key players in the first line of defense offered by the mucosal immune system against invading pathogens. In the present study we sought to determine whether human corneal epithelial cells expressing Toll-like receptors (TLRs) function as pattern-recognition receptors in the innate immune system and, if so, whether these TLRs act as a first line of defense in ocular mucosal immunity. Incubation of human primary corneal epithelial cells and the human corneal epithelial cell line (HCE-T) with peptidoglycan or LPS did not lead to activation, at the level of DNA transcription, of NF-κB or the secretion of inflammation-associated molecules such as IL-6, IL-8, and human β-defensin-2. However, when incubated with IL-1α to activate NF-κB, the production by these cells of such inflammatory mediators was enhanced. Human corneal epithelial cells were observed to express both TLR2- and TLR4-specific mRNA as well as their corresponding proteins intracellularly, but not at the cell surface. However, even when LPS was artificially introduced into the cytoplasm, it did not lead to the activation of epithelial cells. Taken together, our results demonstrate that the intracellular expression of TLR2 and TLR4 in human corneal epithelial cells fails to elicit innate immune responses and therefore, perhaps purposely, contributes to an immunosilent environment at the ocular mucosal epithelium.

Secretory IgA plays a crucial role in the host immune response as a first line of defense. A recent demonstration of in situ IgA class switching in intestinal lamina propria provided an opportunity to reconsider the model for the homing of IgA-committed B cells characterized by distinctive trafficking patterns to effector sites. Those effector sites depend on the organized mucosa-associated lymphoid tissues as their site of induction. In this report we show the preferential presence of IgM+B220+ and IgA+B220+ cells belonging to pre- and post-IgA isotype class-switched cells in the organized mucosa-associated lymphoid tissues, such as nasopharynx-associated lymphoid tissues, isolated lymphoid follicles, and Peyer’s patches, and the defect of those populations in the diffuse effector tissues, such as the nasal passage and intestinal lamina propria. Consistent with these findings, the expressions of a series of IgA isotype class switch recombination-related molecules, including activation-induced cytidine deaminase, Iα-Cμ circle transcripts, and Iα-Cμ circle transcripts, were selectively detected in these organized mucosa-associated lymphoid structures, but not in the diffuse mucosal effector sites. Taken together, these findings suggest that IgA isotype class switching occurs only in the organized mucosa-associated lymphoid organs (e.g., nasopharynx-associated lymphoid tissues, isolated lymphoid follicles, and Peyer’s patches), but not in the diffuse effector tissues of the upper respiratory and gastrointestinal tracts.

Background:Lactobacillus casei strain Shirota (LcS) has been found to exert antiallergic effects in animal experiments, but there is little information about its clinical effects in human patients with allergy. Methods: We performed a randomized double-blind, placebo-controlled study to investigate the effects of LcS in patients with allergic rhinitis triggered by Japanese cedar pollen (JCP). Participants were asked to drink fermented milk containing LcS (LcS group) or placebo (control group) for 8 weeks. Clinical symptoms and immunological parameters were compared between the two groups. Results: Symptom-medication scores (SMS) worsened in accordance with the increase in the amount of scattered JCP. In terms of the nasal and ocular SMS, there was no significant difference between the LcS group and the placebo group during the ingestion period. In the subgroup of patients with moderate-to-severe nasal symptom scores before starting the ingestion of test samples, supplementation with LcS tended to reduce nasal SMS. Conclusion: These results indicate that fermented milk containing LcS does not prevent allergic symptoms in patients sensitive to JCP, but may delay the occurrence of allergic symptoms in patients with moderate-to-severe nasal symptom scores.