Naive murine B cells are known to proliferate and differentiate in response to LPS or CpG, which bind to TLR4 and TLR9, respectively. However, the naive murine B cell compartment is heterogeneous and comprises four different B cell subsets: B-1a, B-1b, marginal zone (MZ), and follicular (FO) B cells. B-1a, B-1b, and MZ B cells are specialized in the response to thymus-independent Ag, and FO B cells are involved in the response to thymus-dependent Ag. This study was undertaken to compare those four naive B cell subsets for their responses to TLR agonists. Quantitative RT-PCR analysis revealed that expression of TLR transcripts differs quantitatively but not qualitatively from one subset to the other. All TLR agonists, with the exception of flagellin and poly(I:C), stimulate B cell proliferation whatever the subset considered. However, TLR ligation leads to massive differentiation of B-1 and MZ B cells into mature plasma cells (PC) but only marginally promotes PC differentiation of FO B cells. Moreover, TLR stimulation strongly up-regulates expression of Blimp-1 and XBP-1S, two transcription factors known to be instrumental in PC differentiation, in B-1 and MZ B cells but not in FO B cells. Altogether, our findings suggest that B-1 and MZ B cells are poised to PC differentiation in response to the microbial environment and that TLR agonists can be instrumental in stimulating Ab-mediated innate immune protection during microbial infections.
Allergic contact dermatitis is the most frequent occupational disease in industrialized countries. It is caused by CD8 + T cell-mediated contact hypersensitivity (CHS) reactions triggered at the site of contact by a variety of chemicals, also known as weak haptens, present in fragrances, dyes, metals, preservatives, and drugs. Despite the myriad of potentially allergenic substances that can penetrate the skin, sensitization is relatively rare and immune tolerance to the substance is often induced by as yet poorly understood mechanisms. Here we show, using the innocuous chemical 2,4-dinitrothiocyanobenzene (DNTB), that cutaneous immune tolerance in mice critically depends on epidermal Langerhans cells (LCs), which capture DNTB and migrate to lymph nodes for direct presentation to CD8 + T cells. Depletion and adoptive transfer experiments revealed that LCs conferred protection from development of CHS by a mechanism involving both anergy and deletion of allergen-specific CD8 + T cells and activation of a population of T cells identified as ICOS + CD4 + Foxp3 + Tregs. Our findings highlight the critical role of LCs in tolerance induction in mice to the prototype innocuous hapten DNTB and suggest that strategies targeting LCs might be valuable for prevention of cutaneous allergy.
Toll-like receptors (TLRs) constitute a family of nonpolymorphic receptors that are devoted to pathogen recognition. In this work, we have explored the impact of TLR ligands (TLR-L) on human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). We show that HSCs and HPCs have a comparable pattern of expression of TLR transcripts characterized by the predominance of TLR1, -2, -3, -4 and -6. In longterm cultures of HSCs, HPCs and stromal cells, most TLR-L profoundly inhibited B-cell development while preserving or enhancing the production of myeloid cells. In short-term cultures, the TLR1/2 ligand PAM 3 CSK 4 induced a large proportion of HPCs to express markers of the myelomonocytic lineage. PAM 3 CSK 4 induced only marginal expression of myeloid lineage markers on HSCs but promoted their myeloid commitment as revealed by their acquisition of the phenotype of multi-and bipotential myeloid progenitors and by upregulation of the transcription factors PU.1, C/EBPa and GATA-1. Our results suggest that TLR agonists can bias the lineage commitment of human HSCs and shift the differentiation of lineage-committed progenitors to favor myelopoiesis at the expense of lymphoid B-cell development.
Dogma holds that plasma cells, as opposed to B cells, cannot bind antigen because they have switched from expression of membrane-bound immunoglobulins (Ig) that constitute the B-cell receptor (BCR) to production of the secreted form of immunoglobulins. Here we compare the phenotypical and functional attributes of plasma cells generated by the T-cell-dependent and T-cell-independent forms of the hapten NP. We show that the nature of the secreted Ig isotype, rather than the chemical structure of the immunizing antigen, defines two functionally distinct populations of plasma cells. Fully mature IgM-expressing plasma cells resident in the bone marrow retain expression of a functional BCR, whereas their IgG+ counterparts do not. Antigen boost modifies the gene expression profile of IgM+ plasma cells and initiates a cytokine production program, characterized by upregulation of CCL5 and IL-10. Our results demonstrate that IgM-expressing plasma cells can sense antigen and acquire competence for cytokine production upon antigenic challenge.
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