Year: 2009
Type: article
Abstract: The development and function of the CD4 T-cell subset that controls B-cell responses to protein antigens has lagged behind our knowledge of other effector lineages of CD4 T cells. Two new studies published in Nature Immunology1, 2 shed light on the requirements for CD4 T cells that are selected for B cell help, and how they mediate that function through the secretion of cytokines. The knowledge that CD4 T cells are required for B cells to produce high-affinity antibodies and generate long-lived responses to most protein antigens (T-dependent antigens) has been appreciated for many years.3 However, CD4 T cells can differentiate into several subsets defined by the specific secretion of cytokines and by the expression of transcription factors that mediate particular functions, suggesting that not all CD4 T cells are engaged in B cell help. More recently, a subset of CD4 T cells, termed follicular helper T cells (TFH cells), has been shown to be primarily responsible for B-cell help during an immune response; separating this population from other CD4 T cell subsets such as Th1 and Th2. TFH cells have largely been defined by their permanent expression of CXCR5, a chemokine receptor required for their migration to the B-cell follicle chemokine CXCL13 and to the germinal center (GC), the main site of B-cell selection, and by the production of the cytokine IL-21.4 The identification of IL-21 secretion by TFH cells suggested that this cytokine would be responsible for B-cell selection and somatic hypermutation; however, studies in IL-21-deficient mice suggested that it was not required for antibody production or GC formation. Moreover, IL-21 seemed to have overlapping roles with IL-4, a cytokine thought to be specific to the Th2 lineage5. In addition, the observation by several groups that IL-4 (as well as IFNγ) played a role in shaping the antibody repertoire clouded our understanding of how TFH cells functioned to mediate B-cell help, and suggested that Th1 and Th2 cells globally secreted cytokines that could also effect B-cell responses. Finally, the requirements for differentiation of TFH cells remained undefined. New studies by Reinhardt et al.,1 and Fazilleau et al.2 answer many of these questions, suggesting a new model for the development of TFH cells. In the former study, the authors take advantage of a sophisticated IL-4 reporter system that has the benefit of tracking both the IL-4-competent and IL-4-secreting CD4 T cells, which develop in the lymph node during an immune response. Interestingly, they find at time points in which B-cell responses are at their peak that all of the IL-4-secreting CD4 T cells are located within GCs, indicating that they are in fact TFH cells, and not Th2 cells. Furthermore, they describe a population of TFH cells in the GC that can also make IFNγ, suggesting that GC B cells compete for cytokine-producing TFH cells, shaping the B-cell selection process and antibody repertoire. By carefully sorting out T–B cell co-conjugates, they show that this is indeed the case. Those B cells in contact with IL-4-secreting TFH cells are largely producing IgG1 or IgE, known isotypes associated with IL-4 production, whereas B cells coupled with IFNγ secreting TFH cells produce IgG2a, an isotype traditionally related to IFNγ sufficiency. This study definitively shows that TFH cells are not limited to IL-21 secretion, and answers the mystery of how Th1- and Th2-associated cytokines can shape the GC-dependent antibody response. In the second study by Fazilleau et al., the authors explore the role of T cell receptor (TCR) affinity in the development of TFH cells, extending their earlier work showing that CD4 T cells with strong affinity for antigen preferentially became a local pool of memory TFH cells. When comparing TFH cells with other effector CD4 T cell subsets, the authors found that CD4 T cells with the highest affinity TCR were more likely to develop into TFH cells than other effector CD4 T cell subsets. This suggested the program that drives TFH-cell differentiation required either strong TCR signaling, or long duration of CD4 T cells with antigen presenting cells in order to fully drive TFH cell development. On the basis of these two studies, we can now extend the model of TFH-cell development and function (Figure 1). On CD4 T-cell encounter with antigen presented by dendritic cells in the T-cell zone, activation will drive competency for the expression of IL-4 or IFNγ, and upregulate the homing receptor CXCR5. Expression of the latter molecule will allow migration of the T cell towards the B-cell follicle, and those CXCR5+ CD4 T cells expressing a TCR with high affinity for antigen will interact with B cells and receive additional signals to become a TFH cell, perhaps including maintenance of CXCR5 expression. Those T cells that do not interact with an antigen-presenting B cell may leave the lymph node and ultimately become a Th1 or Th2 cell. Other studies have shown already that B cells are required for TFH-cell development6, 7 and GC formation,8, 9, 10 specifically through delivery of a ligand signal to inducible T-cell costimulator (ICOS). If TCR affinity and ICOS signals are required, with both derived from dendritic cells or B cells, one question requiring further exploration is that how these two signals integrate to drive a TFH-cell program. One possibility is that expression of a TCR with high affinity for antigen ensures the T cell will have strong and long-lasting interactions with B cells, which may be necessary to deliver other signals, possibly through ICOS, for differentiation into TFH cells. The presence of T–B co-conjugates in vivo is also of particular interest, as studies using methods of tracking live cells in a GC reaction failed to identify many TFH cells that interacted with B cells for any considerable length of time. In fact, TFH cells seemed to move quite quickly in and around the GC, making very few if any contacts with B cells.11, 12, 13 Although the study by Reinhardt et al. shows that IL-4 production has a distinct consequence in shaping B-cell responses, the precise mechanism of how and when this occurs remains to be elucidated. Furthermore, the location and timing of affinity maturation and B-cell selection within the GC is still not well understood, and the role that cytokine-producing TFH cells play in that process is still unknown. Although these studies significantly increase our understanding of TFH-cell development and function, more work is needed to appreciate the mechanisms by which T and B cells drive the antibody response necessary for pathogen elimination and long-lived immune protection. On recognition of antigen, naïve T cells can differentiate into CD62Lhi CCR7hi T lymphoid cells (Tlym) that remain in the T-cell zone, CD62Llo CCR7lo T emigrant cells (Tem) that home to peripheral tissues, or CXCR5hi CD62Llo CCR7lo T resident follicular helper cells (TH). The latter, when given the proper signals from B cells, become T follicular helper cells (TFH) that become cytokine competent after activation by dendritic cells (DCs) and are more likely to have a T cell receptor (TCR) with high affinity for antigen compared with other T effector subsets. Upregulation of CXCR5 allows for their migration to the T–B cell border for encounter with activated B cells that have in turn migrated there in part through upregulation of CCR7. B cells then provide additional signals to T cells, including through antigen-MHC and ICOS, likely driving a full TFH-cell differentiation program and inducing migration into the germinal center (GC) in which secretion of cytokines promotes B-cell selection and affinity maturation.
Source: Immunology and Cell Biology
DOI: 10.1038/icb.2009.26
Authors: Amanda C Poholek, Joe Craft
Institution: Yale University
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Awards: G1120776993, G1614092030, G1880336708
OpenAlex ID: W2065844719