Adam Gulbranson-Judge

The changing preference of T and B cells for partners as T-dependent antibody responses develop

Summary: Recirculating virgin CD4+ T cells spend their life migrating between the T zones of secondary lymphoid tissues where they screen the surface of interdigitating dendritic cells. T‐cell priming starts when processed of interdigitating dendritic cells. T‐cell priming starts when processed peptides or superantigen associated with class II MHC molecules are recognised. Those primed T cells that remain within the lymphoid tissue move of the outer T zone, where they interact with B cells that have taken up and processed antigen. Cognate interaction between these cells initiates immunoglobulin (Ig) class swith‐recombination and proliferation of both B and T cells; much of this growth occurs outside the T zones. B cells both B and T cells; much of this growth occurs outside the T zones. B cells migrate to follicles. Where they form germinal centres, and to extrafollicular sites of B‐cell growth, where they differentiate into mainly short‐lived plasma cells. T cells do not move to the extrafollicular foci but to the follicles; there they proliferate and are subsequently involved in the selection of B cell that have mutated their Ig variable‐region genes. During primary antibody responses T‐cell proliferation in follicles produces many times the peak number of T cell found in that site; a substantial proportion of the CD4+ memory T‐cell pool may originate from growth in follicles.

CD4+CD3− Accessory Cells Costimulate Primed CD4 T Cells through OX40 and CD30 at Sites Where T Cells Collaborate with B Cells

In this report we identify an accessory cell that interacts with primed and memory T cells at sites where they collaborate with B cells. These cells are distinguished from conventional dendritic cells by their lack of response to Flt3 ligand and their inability to process antigen. Unlike dendritic cells, the CD4(+)CD3(-) cells have little CD80 or CD86 expression but do express high levels of the TNF ligands, OX40 ligand and CD30 ligand. We show that Th2-primed cells express the receptors for these TNF ligands and preferentially survive when cocultured with these cells. Furthermore, we show that the preferential survival of OX40(+) T cells and support of memory T cell help for B cells are linked to their association with CD4(+)CD3(-) cells in vivo.

CD4 T cell traffic control: in vivo evidence that ligation of OX40 on CD4 T cells by OX40-ligand expressed on dendritic cells leads to the accumulation of CD4 T cells in B follicles

We report here that CD40‐ but not lipopolysaccharide (LPS)‐activated murine dendritic cells (DC) express OX40‐ligand (OX40L) as has been reported in humans. To understand how OX40 ligation affects differentiation of CD4 T cells at the time of priming, we constitutively expressed OX40L on DC using the DC‐specific promoter of CD11c. Transgenic mice showed greatly increased numbers of CD4 but not CD8 T cells in their B cell areas. This effect was to a great extent immunization dependent, as spleen and lymphoid tissue with no germinal center reactions from mice which had not been deliberately immunized did not show marked CD4 T cell accumulation. The increased numbers of CD4+ CD62low cells in transgenic mice suggest that it is activated CD4 T cells that accumulate within B cell follicles. These data are consistent with the notion that physiological engagement of OX40 (CD134) on activated CD4 T cells either initiates their migration into or causes them to be retained in B follicles. In contrast, LPS‐treated CD did not up‐regulate OX40L expression. This dichotomy provides a molecular explanation of how DC might integrate environmental and accessory signals to control cytokine differentiation and migration in CD4 effector cells.

Co-stimulation and selection for T-cell help for germinal centres: the role of CD28 and OX40

Given the importance of responding to infections with the right defensive strategy, much interest has focused on cytokine differentiation in CD4+ T cells. However, relatively little is known of the logistics of T-cell help for B cells. Here, Lucy Walker and colleagues propose key roles for CD28 and OX40 in coordinating the selection, expansion and migration of CD4+ T cells to B-cell follicles.

γδ T cell help of B cells is induced by repeated parasitic infection, in the absence of other T cells

BACKGROUND gamma delta T cells, like alpha beta T cells, are components of all well-studied vertebrate immune systems. Yet, the contribution of gamma delta T cells to immune responses is poorly characterized. In particular, it has not been resolved whether gamma delta cells, independent of any other T cells, can help B cells produce immunoglobulin and form germinal centers, anatomical foci of specialized T cell-B cell collaboration. RESULTS TCR beta-/- mice, which lack all T cells except gamma delta T cells, routinely displayed higher levels of antibody than fully T cell-deficient mice. Repeated parasitic infection of TCR beta-/- mice, but not of T cell-deficient mice, increased antibody levels and induced germinal centers that contained B cells and monoclonal gamma delta cells in close juxtaposition. However, antibody specificities were more commonly against self than against the challenging pathogen. gamma delta T cell-B cell help was not induced by repeated inoculation of TCR beta-/- mice with mycobacterial antigens. CONCLUSIONS In the absence of any other T cells, gamma delta T cell-B cell collaboration can be significantly enhanced by repeated infection. However, the lack of obvious enrichment for antibodies against the challenging pathogen distinguishes gamma delta T cell help from alpha beta T cell help induced under analogous circumstances. The increased production of generalized antibodies may be particularly relevant to the development of autoimmunity, which commonly occurs in patients suffering from alpha beta T cell deficiencies, such as AIDS.

Defective immunoglobulin class switching in Vav-deficient mice is attributable to compromised T cell help.

Vav, a guanine nucleotide exchange factor for members of the Rho family of small GTPases, is activated through engagement of B and T lymphocyte antigen receptors. It is important for establishing the signaling threshold of the TCR, as mice lacking Vav display defective thymocyte selection. Here, conventional B cells are shown to develop normally in Vav‐deficient mice but these mice have few B‐1 B cells. The threshold for inducing B cell proliferation through BCR engagement in vitro is greater in Vav‐deficient B cells. Nevertheless, in vivo the mutant mice have normal antibody responses to haptenated Ficoll. In contrast, Vav − / − mice show defective class switching to IgG and germinal center formation when immunized with haptenated protein. Interestingly, this defect is reversed in chimeras where normal T cells are present. Antigen‐specific proliferation of T cells in the T zone was found to be similar in wild‐type and Vav − / − mice but the induction of IL‐4 mRNA and switch transcripts was specifically impaired. These results suggest that defective immunoglobulin class switching in Vav‐deficient mice is attributable to compromised T cell help.