Highlights d Germline transcripts peak prior to GC formation and rapidly decline in GCs d IgM-dominated clones are found in late GCs, arguing against ongoing Ig switching d CSR largely ceases upon the onset of somatic hypermutation d CSR decline due to low GLT and APE1 expression is possibly orchestrated by BCL6

To date, not much has been known regarding the role of CD80 and CD86 molecules in signaling of B cells. The CD28/CTLA4 ligands, CD80 (B7-1) and CD86 (B7-2), are expressed on the surface of freshly isolated splenic B cells, and their expression is up-regulated by lipopolysaccharides. In the present study, we have investigated whether signaling via CD80/CD86 could alter the proliferation and immunoglobulin synthesis of B cells. Splenic B cells were stimulated with lipopolysaccharides in the presence of anti-B7-1 (16-10A1) and anti-B7-2 (GL1) monoclonal antibodies (mAbs). Exciting features observed during the study were that cross-linking of CD86 with GL1 enhanced the proliferation and production of IgG1 and IgG2a isotypes. In contrast, anti-B7-1 (16-10A1) mAb could efficiently block the proliferation and production of IgG1 and IgG2a. Furthermore, GL1 mAb could also induce the secretion of IgG isotypes from B cell lymphomas. Importantly, 16-10A1 could retard the growth of lymphomas and favored the up-regulation of pro-apoptotic molecules caspase-3, caspase-8, Fas, FasL, Bak, and Bax and down-regulation of antiapoptotic molecule Bcl-x(L). In contrast, GL1 augmented the level of anti-apoptotic molecules Bcl-w and Bcl-x(L) and decreased the levels of pro-apoptotic molecule caspase-8, thereby providing a novel insight into the mechanism whereby triggering through CD80 and CD86 could deliver regulatory signals. Thus, this study is the first demonstration of a distinct signaling event induced by CD80 and CD86 molecules in B cell lymphoma. Finally, the significance of the finding is that CD80 provided negative signal for the proliferation and IgG secretion of normal B cells and B cell lymphomas. In contrast, CD86 encouraged the activity of B cells.Evidence from a variety of studies has suggested that the B cell contact with T helper cells is important for its optimal activation and responsiveness to cytokines during Ig secretion (1-3). Contact between B and T cells can be mediated by antigen presentation, as well as antigen-independent cell interaction by molecules known as adhesion (LFA-1, LFA-3, ICAM-1, etc.) and costimulatory molecules (CD80, CD86, CD40, etc.) (3-7). Signals from T cells induce two opposite fates in B cells: clonal expansion of B cells that bind specifically to foreign antigens and clonal deletion of equivalent B cells that bind self-antigen. The role of costimulatory molecules is very well established in the activation of T cells (3), but nothing has been determined definitively about how these molecules operate in the activation and differentiation of B cells (8 -10).The best defined co-stimulators to date are two structurally related proteins, . Both of these play a major role in providing costimulation to T cells, leading to their proliferation, cytokine production, and development of effector functions. CD80 and CD86 could also serve as counter-receptors that transduce distinct signal to the antigen-presenting cells upon engagement by CD28 or CTLA-4. The intracellular domains of CD80 and CD86 are ...

Protective high-affinity antibody responses depend on competitive selection of B cells carrying somatically mutated B-cell receptors by follicular helper T (TFH) cells in germinal centres. The rapid T-B-cell interactions that occur during this process are reminiscent of neural synaptic transmission pathways. Here we show that a proportion of human TFH cells contained dense-core granules marked by chromogranin B, which are normally found in neuronal presynaptic terminals storing catecholamines such as dopamine. TFH cells produce high amounts of dopamine and released it upon cognate interaction with B cells. Dopamine causes rapid translocation of intracellular ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) to the B-cell surface, which enhances accumulation of CD40L and chromogranin B granules at the human TFH cell synapse and increases the synapse area. Mathematical modelling suggests that faster dopamine-induced T-B-cell interactions increase total germinal centre output and accelerate it by days. Delivery of neurotransmitters across the T-B-cell synapse may be advantageous in the face of infection.

The most important immunopathological consequence of infection with Leishmania seen in murine and human hosts is the suppression of T cell-mediated immune responses to both mitogens and leishmanial antigens. It has been suggested that this suppression is mediated by macrophages, either by defective antigen processing and presentation or by the elaboration of suppressive mediators like prostaglandins. Optimum activation of T helper cells requires not only T cell receptor occupancy by the antigen-Ia complex, but also costimulatory signals provided by the antigen-presenting cells. We investigated the status of several costimulatory molecules on infected macrophages from both genetically susceptible BALB/c and resistant C57BL/6 mice. Our results demonstrate that upon parasitization, the macrophages become unable to deliver costimulatory signals to T helper cells, and that this effects is mediated by prostaglandins, as the inhibition of its synthesis by indomethacin recovered the defect. Upon infection with L. donovani, B7-1 expression was decreased, while ICAM-1 was marginally increased in BALB/c macrophages and there was no significant change in the expression of B7-1 and ICAM-1 in Leishmania-infected C57BL/6 macrophages. Expression of VCAM-1 did not change during infection. This selective alteration in the expression of costimulatory molecules on L. donovani-infected BALB/c macrophages was caused by the living parasite, as shown by the fact that killing of the parasites by stibogluconate led to no alteration in the levels of costimulatory molecules. We found that the change in B7-1 expression on the surface of infected macrophages resulted in the inhibition of delayed-type hypersensitivity-mediating functions of T helper cells from BALB/c mice. The results described in this study not only throw light on the possible mechanism of leishmanial pathogenesis, but also open up the possibility of immunotherapy of leishmaniasis by selective manipulation of costimulatory molecules.

The most important immunopathological consequence of experimental mycobacterial infection is the suppression of T cell-mediated immune response to both mitogens and mycobacterial antigens. We registered that there was decreased concanavalin A-induced spleen cell proliferation in infected susceptible BALB/c mice as compared to normal mice. In resistant (C3H/HeJ) mice, infection with the bacteria did not induce any suppression in the mitogen-induced lymphoproliferation. Likewise, delayed-type hypersensitivity (DTH) responses, to keyhole limpet hemocyanin and mycobacterial crude soluble antigen were suppressed in infected BALB/c mice but not in C3H/HeJ mice. This depressed T helper cell function may either be due to defective T cell-receptor occupancy by antigen-Ia complex or altered co-stimulatory signals provided by antigen-presenting cells. In the present study, we have investigated the status of certain co-stimulatory molecules on the infected macrophages from both susceptible and resistant mice. Our results demonstrate that upon mycobacterial infection, the macrophages are rendered incapable of delivering the co-stimulatory signals to T helper cells, possibly due to the involvement of prostaglandin, as inhibition of its biosynthesis by indomethacin reversed the defect. Furthermore, the selective regulation was bacteria-induced as killing of the bacteria by rifampicin abrogated the derangements in the expression of co-stimulatory molecules on the Mycobacterium-infected macrophages. Our observations revealed that upon infection with Mycobacterium tuberculosis, B7 was down-regulated while ICAM-1 was increased only in BALB/c but not in C3H/HeJ mice. Expression of VCAM-1 did not change during the infection in either strain of mice. We found that these changes in ICAM-1 and B7 expression on the surface of infected macrophages resulted in inhibition of DTH-mediating functions of T helper cells from BALB/c mice. The results obtained in this study describe not only a novel immune evasion strategy adopted by Mycobacterium, but also open up the possibility of immunotherapy of mycobacterial infection by selective manipulation of co-stimulatory molecules.

Although immune responses against group A streptococci and the heart have been correlated with antibodies and T cell responses against cardiac myosin, there is no unifying hypothesis about carditis caused globally by many different serotypes. Our study identified disease-specific epitopes of human cardiac myosin in the development of rheumatic carditis in humans. We found that immune responses to cardiac myosin were similar in rheumatic carditis among a small sample of worldwide populations, in which immunoglobulin G targeted human cardiac myosin epitopes in the S2 subfragment hinge region within S2 peptides containing amino acid residues 842-992 and 1164-1272. An analysis of rheumatic carditis in a Pacific Islander family confirmed the presence of potential rheumatogenic epitopes in the S2 region of human cardiac myosin. Our report suggests that cardiac myosin epitopes in rheumatic carditis target the S2 region of cardiac myosin and are similar among populations with rheumatic carditis worldwide, regardless of the infecting group A streptococcal M serotype.

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SUMMARYGrowing evidence has supported the conclusion that melatonin, a pineal hormone, modulates the immune function. In our previous study, we evaluated in vivo the potential role of melatonin in the regulation of the antigen specific T and B cells. In the present study, we observe that melatonin downregulated the expression of the co-stimulatory molecule B7-1 but not B7-2 on macrophages. Further, melatonin encouraged the proliferation of anti-CD3 antibody activated CD4 1 T cells only in the presence of antigen-presenting cells and promoted the production of Th2-like cytokines. Furthermore, it failed to influence the activity of B cells in a T-independent manner. Melatonin suppressed the release of TNF-a by LPS or IFN-g activated macrophages but failed to inhibit nitric oxide (NO) release. Thus the study shows that melatonin can engineer the growth of unprimed CD4 1 T cells if both the signals are provided by antigen-presenting cells. However, it could not regulate the function of B cells.