Follicular helper T cells in immune homeostasis

In recent years, follicular helper T (T_FH) cells have become a hot topic for immunologists due to their pivotal role in modulating antibody-mediated immune responses. Although helper T (T_H) 2 cells have long been known to provide help for B-cell responses, T_FH cells have been identified only recently as a distinct lineage of T_H cells that is specific for the provision of help to B cells to generate antibody responses. T_FH cells are distinguished by their unique surface marker expression (CXCR5^high, PD-1^high, ICOS^high and CCR7^low), cytokine profile (IL-21 and IL-6) and, more importantly, transcriptional factor expression (Bcl6). Furthermore, T_FH cells are endowed with the capacity to migrate to B-cell follicles in secondary lymphoid organs and closely interact with B cells to promote the formation of germinal centers (GCs). The stable cognate interaction between T_FH and B cells in the GC is mutually beneficial to them for their development and function. Specifically, T_FH cells help B cells produce long-lived memory B cells and high-affinity antibodies and, in reciprocation, they are helped by B cells for further differentiation through cell cognation. This is how effective antibody responses are generated to provide protection against pathogenic microbes.

In this issue, there are three reviews to update the study on the biology of T_FH cells with a focus on the involvement of these cells in disease settings.^1,2,3 Chen et al.¹ provide an overview of the up-to-date knowledge on ontological and physiological properties of T_FH cells. Shekhar and Yang² have reviewed the current literature on the role of T_FH cells in pathologies, including autoimmunity and immunodeficiency; whereas, Kemeny³ discusses the contribution of T_FH cells to the pathogenesis of allergic diseases. The function of T_FH cells is beneficial to the host in that it helps establish the humoral arm of adaptive immunity to fight against the invasion of pathogens. Although the benefit is obvious, the ‘dark’ side of these cells has also started to be recognized. In addition to the significant progress in T_FH cell biology, including cellular and molecular characterization, distribution and mechanistic study on signaling and antibody class switching, recent studies on T_FH cells have now expanded to various disease settings, such as autoimmune diseases, immunodeficiency, lymphoma, asthma and other allergic diseases. The studies on autoimmunity are extensively performed in various types of lupus-prone mouse models with considerable amount of work on human patients. The data on allergic diseases are mostly from immunoglobulin E (IgE) responses, especially via the involvement of IL-21.

The contribution of T_FH cells in the development of autoimmunity and allergic diseases suggests the importance of a balanced response of this T-cell subset in maintaining immune homeostasis. However, the mechanism for maintaining this balance remains largely unclear. The identification of follicular regulatory T (T_FR) cells, which are involved in the regulation of T_FH cell development and function, has shed some light on this field.^4,5 Notably, T_FR cells express FoxP3 and CTLA-4 and produce IL-10, like classic regulatory T (T_REG) cells, but they depend on Bcl6 for their development and express CXCR5, as do classic T_FH cells. These FoxP3⁺ T_FR cells are found to inhibit GC responses, preventing exaggerated GC maturation and antibody development. It is likely that at least a portion of the lupus-prone mice and humans have deficiencies in the development and/or function of T_FR cells. Moreover, the identification of CD8⁺ T_REG cells in GC and the modulating effect of these cells on T_FH cell development and function emphasizes on the importance of networking of different cell types in maintaining the homeostasis of the immune system.⁶ In addition to the lack of regulation by T_FR cells, intrinsic hyper T_FH cell responses may exist in the individuals with autoimmunity, which may be involved in Bcl6 and Blimp1 dysregulation. By the same token, the deficiency in T_FH cells in some immunodeficiency diseases may also be related to the imbalance of these transcriptional factors. Further study on the balance of T_FH and T_FR cells especially in the setting of B-cell follicle and GC appears to be crucial for understanding the pathogenesis, and development of new therapeutic approaches to these diseases.

The studies on the role of T_FH cells in allergic diseases are mainly based on the responses of IgE antibody, which is the typical antibody isotype mediating allergic diseases including allergic asthma.² It has been long recognized that IL-4 and CD40–CD40L interactions are critical for IgE responses. T_FH cells can produce IL-4 and express CD40L, which are sufficient to promote IgE responses. However, recent studies suggest that IL-21, the most typical cytokine of T_FH cells, is critical for IgE responses. In fact, it appears that IL-21 plays a critical role in T_FH cell-mediated help for B cells in somatic mutation and isotype class switching. Given the fact that class switching for different antibody isotypes requires different types of cytokines, i.e., IL-4 for IgE, interferon-γ for IgG2a, transforming growth factor-β and IL-6 for IgA, it is unlikely that a single T_FH cell can produce all of the different types of cytokines. This raises a question if T_FH cells consist of different subsets which have common features of T_FH cells, particularly IL-21 production, but exhibit differential T_H1, T_H2 and T_REG cell cytokine patterns. This is an important question to address in future studies, not only for allergic diseases, but also for infectious diseases, considering the significant difference of the various isotypes of antibody in pathogen neutralization, opsonization and antibody-dependent cytotoxicity.

Notably, but not surprisingly, most of the mechanistic studies on T_FH cells in disease settings are performed in animal models, particularly the mouse. Considering the functional site of T_FH cells, GC, it is rather difficult to perform studies focusing on local responses in humans. The human studies so far are virtually all from studies on circulating T_FH (cT_FH) cells. Interestingly, cT_FH cells, which are identified in a study involving systemic lupus erythematosus patients, express CXCR5, ICOS and PD-1, but not BCL6 and IL-21.⁷ Given that BCL6 and IL-21 are the most critical transcription factor and cytokine for T_FH cell development and function, it is still debatable as to what degree the cT_FH cells represent GC T_FH cells. Further study on the correlation and difference between T_FH cells in peripheral blood and secondary lymphoid organs is needed.

Recent studies have provided significant evidence on the role of T_FH cells in protective and pathological immune responses, although much remains to be known. T_FH cells play a critical role in eliciting effective antibody responses during vaccination or infection; whereas, dysregulation of these cells can lead to pathologies, such as autoimmunity and allergy. However, many questions remain concerning the mechanisms of how the function of T_FH cells is regulated to avoid development of diseases and maintain immune homeostasis. What are the factors that trigger T_FH cell differentiation? What are the molecular events that result in dysregulation of T_FH cells? How do T_FR cells and other regulatory cells interact with T_FH cells to maintain humoral immune tolerance? Are there subsets of T_FH cells that are destined to perform different functions including isotype switches? Are cT_FH cells indeed related to classic GC T_FH cells? Can T_FH/cT_FH cells be used as diagnostic and monitoring markers for diseases like lymphoma? To what extent the findings from mouse studies can be relevant to humans? Future studies need to answer these questions, which may have implications for designing the prophylactic and/or therapeutic strategies against these diseases.