Regulatory T cells (Tregs) can potentially migrate to the B cell areas of secondary lymphoid tissues and suppress T cell-dependent B cell Ig response. T cell-dependent Ig response requires B cell stimulation by Th cells. It has been unknown whether Tregs can directly suppress B cells or whether they must suppress Th cells to suppress B cell response. We report here that Foxp3+ Tregs are found in T-B area borders and within germinal centers of human lymphoid tissues and can directly suppress B cell Ig response. Although Tregs can effectively suppress T cells, they can also directly suppress B cell response without the need to first suppress Th cells. The direct suppression of B cell Ig production by Tregs is accompanied by inhibition of Ig class switch recombination.

IntroductionHeterogeneous subsets of CD4 ϩ T cells are master regulators of immune responses. Diverse memory and effector CD4 ϩ T-cell subsets originate from naive T cells. Naive T cells, generated in the thymus, keep circulating the blood and secondary lymphoid tissues in search of antigens. [1][2][3] In secondary lymphoid tissues, naive T cells undergo activation, clonal expansion, and differentiation to become memory and effector cells in response to antigenic signals provided by antigen presenting cells. 4 Many memory and effector T cells migrate to peripheral nonlymphoid tissues for immune surveillance. 5,6 Depending on their effector function and cytokine production capacity, conventional memory and effector T cells are divided into nonpolarized T cells, T helper 1 (Th1), Th2, and regulatory T cells. 7-10 They are also classified into "central memory cells" best characterized as CXCR5 ϩ CCR7 ϩ cells and "effector memory cells" enriched among CCR7 Ϫ T cells. 11 CCR7 Ϫ memory T cells contain a higher frequency of cells producing Th1 and Th2 cytokines than CXCR5 ϩ CCR7 ϩ memory T cells upon T-cell receptor (TCR) stimulation, thus closer to effector T cells in cytokine production. 12 Recently, another CD4 ϩ T-cell subset, distinct from polarized Th1 and Th2 cells in cytokine production, migration, and effector function, has been characterized. 13 In human lymphoid tissues, CD4 ϩ T cells expressing CXCR5 and CD57 are specifically localized in germinal centers (termed GC-Th cells hereafter). 13,14 These T cells are related to other CXCR5 ϩ memory T cells 15,16 in that they are mostly nonpolarized (lacking interleukin 4 [IL-4] and interferon ␥ [IFN-␥] production) but are efficient in inducing B-cell production of immunoglobulin. 13 In mice, a similar type of T cells exists with efficient B-cell helping capacity but no inflammatory immune response. 17 GC-Th cells lack CCR7, a T-cell area localization receptor, and do not migrate to ELC/CCL19 but migrate toward the B-cell area chemokine CXCL13, a feature consistent with their specific localization in germinal centers. 13 In a search for the molecular basis for the differences between GC-Th cells and other T-cell subsets (CXCR5 ϩ CCR7 ϩ early or central memory and CCR7 Ϫ effector memory cells), we compared their gene expression profiles with a cDNA microarray technique using naive cells as reference cells. GC-Th cells display unique gene expression patterns not only on the global scale but also in several major gene groups such as effector molecules (cytokine and chemokine), cell cycle and apoptosis, transcription factors, and migration. Most striking is the selective and high-level expression of a potent B-cell-and CXCR5 ϩ T-cell-attracting chemokine, CXCL13, in GC-Th cells. CXCL13 production by GC-Th cells is induced by TCR activation and is dependent on the costimulation signal through CD28. The significance of the unique gene expression profile of GC-Th cells in their biology and function in germinal centers is discussed herein. Materials and methods Cell isolat...

No abstract

It is a question of interest whether Th17 cells express trafficking receptors unique to this Th cell lineage and migrate specifically to certain tissue sites. We found several Th17 cell subsets at different developing stages in a human secondary lymphoid organ (tonsils) and adult, but not in neonatal, blood. These Th17 cell subsets include a novel in vivo-stimulated tonsil IL17+ T cell subset detected without any artificial stimulation in vitro. We investigated in depth the trafficking receptor phenotype of the Th17 cell subsets in tonsils and adult blood. The developing Th17 cells in tonsils highly expressed both Th1- (CCR2, CXCR3, CCR5, and CXCR6) and Th2-associated (CCR4) trafficking receptors. Moreover, Th17 cells share major non-lymphoid tissue trafficking receptors, such as CCR4, CCR5, CCR6, CXCR3, and CXCR6, with FOXP3+ T regulatory cells. In addition, many Th17 cells express homeostatic chemokine receptors (CD62L, CCR6, CCR7, CXCR4, and CXCR5) implicated in T cell migration to and within lymphoid tissues. Expression of CCR6 and CCR4 by some Th17 cells is not a feature unique to Th17 cells but shared with FOXP3+ T cells. Interestingly, the IL17+IFN-γ+ Th17 cells have the features of both IL17−IFN-γ+ Th1 and IL17+IFN-γ− Th17 cells in expression of trafficking receptors. Taken together, our results revealed that Th17 cells are highly heterogeneous, in terms of trafficking receptors, and programmed to share major trafficking receptors with other T cell lineages. These findings have important implications in their distribution in the human body in relation to other regulatory T cell subsets.