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A second cohort of animals was left to clear the infection, in order to quantify the development of cytokine-secreting memory T cells. T cells from week 7 post-infection were re-stimulated as previously. As MD4 mice clear bacteria less efficiently Figure 3B than wild type mice we also carried out experiments in which the mice were treated with antibiotic from the peak of infection for 10 days. Supplemental Fig.
Our demonstration that primary T cell responses were influenced by B cells in an antigen non-specific manner while memory T cell responses were dependent upon BCR suggests antigen presentation by B cells is dispensable at early stages but crucial later on. Primary T cell responses to Salmonella in these mice, as in BCR-irrelevant mice, were found to be largely normal Figure 4 and were sufficient to allow bacterial clearance.
To test if this failure of Th1 memory development influenced the protection, we challenged the mice, 12 weeks later, with a virulent Salmonella strain and found that they survived less well than controls Supplemental Fig. The IL response was not altered. T cell cytokine response was not completely absent in the cytokine chimera, so we conclude that B cell derived cytokines play an important but supporting role.
Data shown in A were representative of 8 independent experiments and in B of 6 independent experiments. All the cytokine chimeras cleared bacteria normally.
In this study we have identified two distinct and functionally separable phases of the B cell contribution to T cell differentiation during a response to an ongoing Salmonella infection. B cell cytokine production is largely MyDdependent and we propose that the early influence of B cells on the developing CD4 T cell response is mediated by cytokines produced in response to TLR ligation. In support of this we show that when B cells are incapable of making certain cytokines eg.
Th1 and Th We do not know if the B cell-derived cytokines act directly on activated T cells or on other cell types that influence T cell differentiation.
In the absence of this cognate phase of B-T cell interaction, the protective Th1 memory cell response fails to develop. Evidence of the importance of B cells in the development of CD4 T cell memory has accumulated over several years in studies using protein antigens and TCR transgenic models 13 , 17 , The data presented here along with other recent studies 14 - 16 , 18 , 63 , shows, during infection, the failure to develop T cell memory in the absence of antibody-independent B cell function.
This means that other APC eg. DC are competent and sufficient to drive the primary response, strongly suggesting that, as the response to Salmonella antigens proceeds, the participating APC changes from the DC, initially, to B cells later on. Antibody seems to play no significant role in enhancing Ag-presentation during the primary response, as provision of anti- Salmonella antibodies to the MD4 mice did not alter the magnitude or the longevity of their primary response.
As we did not identify individual antigen-specific memory T cells in this study, we can say little about memory T cell survival. Our definition, of memory here is a functional one in which we detect enhanced responsiveness to antigen recall.
Thus, we do not know if the memory we see is mediated by bona fide memory T cells or long-lived effectors, but given that systemic CD4 T cell memory is not apparent in some mice eg. Future studies using Salmonella that expressing a peptide epitope detectable using MHC II tetramers will address events at a cellular level. In previous work from this lab 13 , we showed that antigen presentation by B cells affected the T cell response as early as day post-immunization, somewhat earlier than we indicate here.
The two studies differ in antigen delivery, here we follow the primary response to bacterial infection, and this may lead to enhanced APC activation in comparison to protein immunization with adjuvant. Taken together, these data indicate that in vivo the contribution of DC is time-limited and cannot lead to optimal memory cell development.
Ahmed and colleagues 18 also saw rapid decline within 3 weeks of LCMV-specific CD4 T cell response in B cell-deficient mice and concluded that B cell involvement is in the establishment and maintenance phase of CD4 T cell memory; we would agree.
The majority of published studies that have addressed the influence of B cells on T cell differentiation have noted their involvement in Th2 responses 32 - 35 , Here we show a clear contribution of B cells to the development of an effective Th1 and Th17 response to Salmonella infection.
As discussed above, for Th1 memory this relates to continued APC function. Despite this, the presence of B cells does have a measurable effect on the development of polarised Th subsets. We investigated the cytokines, known to be secreted by B cells after TLR activation An obvious candidate Th1 polarising cytokine is IL, however, mouse B cells make very little ILp40 39 and chimeras in which B cells lack IL, exhibit completely normal primary and memory Th1 responses to Salmonella not shown.
We show here a direct effect of B cell cytokines on the development of effector T cell responses during infection. The worry that the use of B cell depletion therapy in autoimmune patients might have consequences for infection is only exacerbated by these data, as B cells, in addition to antibody production, also support the differentiation of inflammatory, protective Th1 and Th17 responses. The adaptive B cell response including APC function becomes absolutely crucial later days for sustaining the effector T cell response and enabling memory T cell formation.
It will be intriguing to discover where these two distinct phases of the B cell dependent T cell response occur within lymphoid tissues.
We conclude that a complete and rounded CD4 T cell response is dependent on B cells. National Center for Biotechnology Information , U. J Immunol. Author manuscript; available in PMC Aug Tom A. Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available free at J Immunol. See other articles in PMC that cite the published article. Abstract Protective Th1 responses to Salmonella enterica do not develop in the absence of B cells.
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Abstract Available from publisher site using DOI. A subscription may be required. Gerondakis S 1 ,. Grumont RJ ,. Ashish Banerjee Search articles by 'Ashish Banerjee'. Banerjee A. Affiliations 1 author 1.
Share this article Share with email Share with twitter Share with linkedin Share with facebook. Abstract Following encounters with microbes, cellular activation programs that involve the control of proliferation and survival are initiated in follicular B cells either via the B-cell receptor in a specific antigen-defined manner, or through Toll-like receptors TLRs that recognize specific microbial products.
This review summarizes and discusses recent findings that shed light on how the nuclear factor kappaB pathway controls and coordinates B-cell division and survival following TLR4 engagement.
Full text links Read article at publisher's site DOI : References Articles referenced by this article 29 The toll-like receptor protein RP regulates lipopolysaccharide signaling in B cells. Toll-like receptor signaling pathways. N2 - Following encounters with microbes, cellular activation programs that involve the control of proliferation and survival are initiated in follicular B cells either via the B-cell receptor in a specific antigen-defined manner, or through Toll-like receptors TLRs that recognize specific microbial products.
AB - Following encounters with microbes, cellular activation programs that involve the control of proliferation and survival are initiated in follicular B cells either via the B-cell receptor in a specific antigen-defined manner, or through Toll-like receptors TLRs that recognize specific microbial products.
Abstract Following encounters with microbes, cellular activation programs that involve the control of proliferation and survival are initiated in follicular B cells either via the B-cell receptor in a specific antigen-defined manner, or through Toll-like receptors TLRs that recognize specific microbial products.
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