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      Cytokine-secreting follicular T cells shape the antibody repertoire

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          Abstract

          High-affinity antibodies are critical for host protection and underlie successful vaccines. Generation of such antibodies requires T cell-dependent help, which mediates germinal center (GC) reactions where mutation and selection of B cells occurs. Using an interleukin 4 (IL-4)-reporter system, we show that follicular CD4 + T (T FH) cells comprised essentially all of the cytokine-secreting T cells in lymph nodes and were functionally distinct from T cells secreting the same cytokine in peripheral tissues. T FH cells with different cytokine profiles could be isolated as conjugates with B cells undergoing cytokine-specific immunoglobulin class-switching with evidence of somatic hypermutation. These findings subport a model wherein B cells compete for cytokines produced by T FH cells that shape the affinity and isotype of the antibody response.

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          Most cited references 31

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          Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.

          Induced overexpression of AID in CH12F3-2 B lymphoma cells augmented class switching from IgM to IgA without cytokine stimulation. AID deficiency caused a complete defect in class switching and showed a hyper-IgM phenotype with enlarged germinal centers containing strongly activated B cells before or after immunization. AID-/- spleen cells stimulated in vitro with LPS and cytokines failed to undergo class switch recombination although they expressed germline transcripts. Immunization of AID-/- chimera with 4-hydroxy-3-nitrophenylacetyl (NP) chicken gamma-globulin induced neither accumulation of mutations in the NP-specific variable region gene nor class switching. These results suggest that AID may be involved in regulation or catalysis of the DNA modification step of both class switching and somatic hypermutation.
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            Fcgamma receptors: old friends and new family members.

            Although cellular receptors for immunoglobulins were first identified nearly 40 years ago, their central role in the immune response was discovered only in the last decade. They are key players in both the afferent and efferent phase of an immune response, setting thresholds for B cell activation, regulating the maturation of dendritic cells, and coupling the exquisite specificity of the antibody response to innate effector pathways, such as phagocytosis, antibody-dependent cellular cytotoxicity, and the recruitment and activation of inflammatory cells. Moreover, because of their general presence as receptor pairs consisting of activating and inhibitory molecules on the same cell, they have become a paradigm for studying the balance of positive and negative signals that ultimately determine the outcome of an immune response. This review will summarize recent results in Fc-receptor biology with an emphasis on data obtained in in vivo model systems.
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              A fundamental role for interleukin-21 in the generation of T follicular helper cells.

              T cell help to B cells is a fundamental property of adaptive immunity, yet only recently have many of the cellular and molecular mechanisms of T cell help emerged. T follicular helper (Tfh) cells are the CD4(+) T helper cells that provide cognate help to B cells for high-affinity antibody production in germinal centers (GC). Tfh cells produce interleukin-21 (IL-21), and we show that IL-21 was necessary for GC formation. However, the central role of IL-21 in GC formation reflected its effects on Tfh cell generation rather than on B cells. Expression of the inducible costimulator (ICOS) was necessary for optimal production of IL-21, indicative of interplay between these two Tfh cell-expressed molecules. Finally, we demonstrate that IL-21's costimulatory capacity for T helper cell differentiation operated at the level of the T cell receptor signalosome through Vav1, a signaling molecule that controls T cell helper function. This study reveals a previously unappreciated role for Tfh cells in the formation of the GC and isotype switching through a CD4(+) T cell-intrinsic requirement for IL-21.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nature immunology
                1529-2908
                1529-2916
                18 March 2009
                1 March 2009
                April 2009
                1 October 2009
                : 10
                : 4
                : 385-393
                Affiliations
                [1 ]Howard Hughes Medical Institute and Departments of Medicine and Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143
                Author notes
                Correspondence should be addressed to R. M. L., ( locksley@ 123456medicine.ucsf.edu )
                Article
                nihpa99293
                10.1038/ni.1715
                2714053
                19252490
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: Howard Hughes Medical Institute
                Award ID: U19 AI077439-01 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: Howard Hughes Medical Institute
                Award ID: R37 AI026918-21 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: Howard Hughes Medical Institute
                Award ID: ||HHMI_
                Categories
                Article

                Immunology

                th1/th2 cells, cytokines, b cell selection, germinal center, follicular helper t cells

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