Germinal Center B Cells Constitute a Predominant Physiological Source of IL-4: Implication for Th2 Development In Vivo

Abstract

Protective immunity depends upon the capability of the immune system to properly adapt the response to the nature of an infectious agent. CD4+ Th cells are implicated in this orchestration by secreting a polarized pattern of cytokines. Although Th2 development in animal models and in human cells in vitro to a large extent depends on IL-4, the nature of the cells that provide the initial IL-4 in vivo is still elusive. In this report, we describe the anatomical localization as well as the identity of IL-4-producing cells in human tonsil, a representative secondary lymphoid organ. We demonstrate that IL-4 production is a normal and intrinsic feature of germinal center (GC) B cells. We also show that expression of IL-4 is highly confined to the GCs, in which the B cells constitute the prevalent cellular source. Furthermore, immunofluorescence analysis of colon mucosa reveals a strikingly similar pattern of IL-4-expressing cells compared with tonsils, demonstrating that IL-4 production from GC B cells is not a unique feature of the upper respiratory tract. Our results show that GCs provide the most appropriate microenvironment for IL-4-dependent Th2 polarization in vivo and imply a critical role for GC B cells in this differentiation process.

Germinal Centers Regulate Human Th2 Development

“…Accordingly, follicular CD4 ϩ T cells, initially primed on T cell zone-localized dendritic cells (DCs), are likely to receive a second boost of differentiation signals during the interaction with GC B cells. We have recently shown that GC B cells produce IL-4 in vivo, suggesting that GCs do provide an appropriate microenvironment for Th2 development (25). In this study we demonstrate that although CD4 ϩ T cells from human tonsil lack immediate effector functions, they develop into cytokine-secreting cells after polyclonal activation in vitro.…”

“…We have recently shown that IL-4 production in human mucosaassociated lymphoid tissues is highly confined to GCs where B cells constitute a predominant cellular source (25). In response to platelet activating factor, GC B cells also secrete relatively large amounts of IL-4 in vitro (37).…”

Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy

“…One scenario is that during B cell repopulation, stochastic events and environmental hits fail to converge and reproduce the breakdown of tolerance characteristic of the initial disease. Alternatively, the absence of B cells could create profound changes in other immune cells, including T cell subsets (altered T helper cell polarization, defective migration of CXCR5ϩ follicular T helper cells, or T regulatory cell expansion) (7,8,(38)(39)(40) and DCs (9), as has been suggested in recent studies (41,42). Finally, a reconstitution dominated by immature and virgin B cells may lead preferentially to T cell anergy (10).…”

DNA Vaccines, Combining Form of Antigen and Method of Delivery to Raise a Spectrum of IFN-γ and IL-4-Producing CD4+ and CD8+ T Cells

“…Secreted Ags can undergo Ag processing and presentation following receptor-mediated uptake into B cells, either through Ag-specific Ig (28,29) or other receptors such as the transferrin receptor (30). B cells, especially germinal center B cells, are strong producers of IL-4, the lymphokine that determines the raising of type 2 CD4 ϩ T cell responses (31,32). Also, it is known that when B cells are ablated, the generation of IFN-␥-producing CD4 ϩ T cells is increased (33).…”