Preferential Generation of Follicular B Helper T Cells from Foxp3+ T Cells in Gut Peyer's Patches

Most of the immunoglobulin A (IgA) in the gut is generated by B cells in the germinal centers of Peyer's patches through a process that requires the presence of CD4+ follicular B helper T(TFH) cells. The nature of these TFH cells in Peyer's patches has been elusive. Here, we demonstrate that suppressive Foxp3+CD4+ T cells can differentiate into TFH cells in mouse Peyer's patches. The conversion of Foxp3+ T cells into TFH cells requires the loss of Foxp3 expression and subsequent interaction with B cells. Thus, environmental cues present in gut Peyer's patches promote the selective differentiation of distinct helper T cell subsets, such as TFH cells.

[1]  B. Malissen,et al.  Heterogeneity of natural Foxp3+ T cells: A committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity , 2009, Proceedings of the National Academy of Sciences.

[2]  Keiichiro Suzuki,et al.  Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. , 2008, Immunity.

[3]  D. Hwang,et al.  Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. , 2008, Immunity.

[4]  Chen Dong,et al.  Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. , 2008, Immunity.

[5]  C. Mackay,et al.  A fundamental role for interleukin-21 in the generation of T follicular helper cells. , 2008, Immunity.

[6]  P. Perrin,et al.  Th2 Lymphoproliferative Disorder of LatY136F Mutant Mice Unfolds Independently of TCR-MHC Engagement and Is Insensitive to the Action of Foxp3+ Regulatory T Cells1 , 2008, The Journal of Immunology.

[7]  J. Cyster,et al.  Role of CXCR5 and CCR7 in Follicular Th Cell Positioning and Appearance of a Programmed Cell Death Gene-1High Germinal Center-Associated Subpopulation1 , 2007, The Journal of Immunology.

[8]  R. Noelle,et al.  All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation , 2007, The Journal of experimental medicine.

[9]  Y. Belkaid,et al.  A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism , 2007, The Journal of experimental medicine.

[10]  Y. Belkaid,et al.  Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid , 2007, The Journal of experimental medicine.

[11]  Hilde Cheroutre,et al.  Reciprocal TH17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid , 2007, Science.

[12]  Vincent C. Manganiello,et al.  Foxp3-dependent programme of regulatory T-cell differentiation , 2007, Nature.

[13]  Edgar Schmitt,et al.  Epigenetic Control of the foxp3 Locus in Regulatory T Cells , 2007, PLoS biology.

[14]  D. Littman,et al.  The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells , 2006, Cell.

[15]  K. Murphy,et al.  Th17: an effector CD4 T cell lineage with regulatory T cell ties. , 2006, Immunity.

[16]  C. Mackay,et al.  Follicular B helper T cells in antibody responses and autoimmunity , 2005, Nature Reviews Immunology.

[17]  D. Gray,et al.  T Cell Accumulation in B Cell Follicles Is Regulated by Dendritic Cells and Is Independent of B Cell Activation , 2003, The Journal of experimental medicine.

[18]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2002 .

[19]  T. Honjo,et al.  In situ class switching and differentiation to IgA-producing cells in the gut lamina propria , 2001, Nature.

[20]  P. Loetscher,et al.  Cxc Chemokine Receptor 5 Expression Defines Follicular Homing T Cells with B Cell Helper Function , 2000, The Journal of experimental medicine.

[21]  Federica Sallusto,et al.  Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production , 2000, The Journal of experimental medicine.

[22]  P. Lane,et al.  Compromised Ox40 Function in Cd28-Deficient Mice Is Linked with Failure to Develop Cxc Chemokine Receptor 5–Positive Cd4 Cells and Germinal Centers , 1999, The Journal of experimental medicine.

[23]  Fiona Powrie,et al.  An Essential Role for Interleukin 10 in the Function of Regulatory T Cells That Inhibit Intestinal Inflammation , 1999, The Journal of experimental medicine.

[24]  T. Honjo,et al.  Specific Expression of Activation-induced Cytidine Deaminase (AID), a Novel Member of the RNA-editing Deaminase Family in Germinal Center B Cells* , 1999, The Journal of Biological Chemistry.

[25]  W. Pao,et al.  Germinal center formation, immunoglobulin class switching, and autoantibody production driven by "non alpha/beta" T cells , 1996, The Journal of experimental medicine.

[26]  A. Aruffo,et al.  gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory , 1994, The Journal of experimental medicine.

[27]  S. Fagarasan.  Intestinal IgA synthesis: a primitive form of adaptive immunity that regulates microbial communities in the gut. , 2006, Current topics in microbiology and immunology.

[28]  A. Macpherson.  IgA adaptation to the presence of commensal bacteria in the intestine. , 2006, Current topics in microbiology and immunology.