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The origins, function, and regulation of T follicular helper cells.

Ma CS, Deenick EK, Batten M, Tangye SG - J. Exp. Med. (2012)

Bottom Line: Ab responses against most antigens (Ags) require interactions between B cells and CD4(+) T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell-dependent B cell responses.Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy.Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.

View Article: PubMed Central - HTML - PubMed

Affiliation: Immunology Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.

ABSTRACT
The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization and clearance of pathogens and subsequent host survival after natural infection with a variety of microorganisms. Most currently available vaccines rely on the induction of long-lived protective humoral immune responses by memory B cells and plasma cells, underscoring the importance of Abs in host protection. Ab responses against most antigens (Ags) require interactions between B cells and CD4(+) T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell-dependent B cell responses. Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.

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Molecular regulation of Tfh development. Tfh development requires the integrated and balanced function of numerous transcription factors. BATF acts proximally by inducing Bcl-6 and c-Maf. Bcl-6 imprints a Tfh fate by suppressing expression and/or function of transcriptional regulators of alternate effector fates (i.e., Tbx21 [Th1], Gata3 [Th2], and Rorc [Th17]), microRNAs that suppress Tfh generation, and Prdm1 (encoding Blimp-1), which directly suppresses Bcl-6. c-Maf contributes to Tfh cells by inducing CXCR5 and IL-21. STAT3-activating cytokines IL-6, IL-21, and IL-27 can also induce c-Maf, and STAT3 can directly induce IL-21. IL-12 induces IL-21 in a STAT3-dependent manner, but it is unknown whether this involves c-Maf or is a direct effect of STAT3. Tfh generation is restricted by Blimp-1, which is induced by IL-2 in a STAT5-dependent manner and blocks Bcl-6 expression, and by T-bet (induced by IL-12), which physically associates with Bcl-6 and prevents Bcl-6–dependent repression.
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fig2: Molecular regulation of Tfh development. Tfh development requires the integrated and balanced function of numerous transcription factors. BATF acts proximally by inducing Bcl-6 and c-Maf. Bcl-6 imprints a Tfh fate by suppressing expression and/or function of transcriptional regulators of alternate effector fates (i.e., Tbx21 [Th1], Gata3 [Th2], and Rorc [Th17]), microRNAs that suppress Tfh generation, and Prdm1 (encoding Blimp-1), which directly suppresses Bcl-6. c-Maf contributes to Tfh cells by inducing CXCR5 and IL-21. STAT3-activating cytokines IL-6, IL-21, and IL-27 can also induce c-Maf, and STAT3 can directly induce IL-21. IL-12 induces IL-21 in a STAT3-dependent manner, but it is unknown whether this involves c-Maf or is a direct effect of STAT3. Tfh generation is restricted by Blimp-1, which is induced by IL-2 in a STAT5-dependent manner and blocks Bcl-6 expression, and by T-bet (induced by IL-12), which physically associates with Bcl-6 and prevents Bcl-6–dependent repression.

Mentions: Bcl-6 functions as a transcriptional repressor. Thus, it was initially difficult to invoke a mechanism by which Bcl-6 actively drives a Tfh program in naive CD4+ T cells. However, several scenarios have now been proposed. As Bcl-6 suppresses GATA3 expression and Th2 responses (Kusam et al., 2003), it could promote Tfh differentiation by interfering with the expression or function of transcription factors that control alternate Th cell fates (Fig. 2). Indeed, enforced expression of Bcl-6 in naive CD4+ T cells cultured under Th1 or Th17 conditions reduces the proportion of IFN-γ− or IL-17–expressing cells (Nurieva et al., 2009; Yu et al., 2009), most likely caused by its ability to bind to consensus sites in the promoters of Tbx21 and Rorc (encoding RORγt), and thus reduce protein expression and/or function. This is consistent with the enhanced generation of Tfh cells from Tbx21-deficient CD4+ T cells both in vivo and in vitro (Nakayamada et al., 2011; Oestreich et al., 2012).


The origins, function, and regulation of T follicular helper cells.

Ma CS, Deenick EK, Batten M, Tangye SG - J. Exp. Med. (2012)

Molecular regulation of Tfh development. Tfh development requires the integrated and balanced function of numerous transcription factors. BATF acts proximally by inducing Bcl-6 and c-Maf. Bcl-6 imprints a Tfh fate by suppressing expression and/or function of transcriptional regulators of alternate effector fates (i.e., Tbx21 [Th1], Gata3 [Th2], and Rorc [Th17]), microRNAs that suppress Tfh generation, and Prdm1 (encoding Blimp-1), which directly suppresses Bcl-6. c-Maf contributes to Tfh cells by inducing CXCR5 and IL-21. STAT3-activating cytokines IL-6, IL-21, and IL-27 can also induce c-Maf, and STAT3 can directly induce IL-21. IL-12 induces IL-21 in a STAT3-dependent manner, but it is unknown whether this involves c-Maf or is a direct effect of STAT3. Tfh generation is restricted by Blimp-1, which is induced by IL-2 in a STAT5-dependent manner and blocks Bcl-6 expression, and by T-bet (induced by IL-12), which physically associates with Bcl-6 and prevents Bcl-6–dependent repression.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3405510&req=5

fig2: Molecular regulation of Tfh development. Tfh development requires the integrated and balanced function of numerous transcription factors. BATF acts proximally by inducing Bcl-6 and c-Maf. Bcl-6 imprints a Tfh fate by suppressing expression and/or function of transcriptional regulators of alternate effector fates (i.e., Tbx21 [Th1], Gata3 [Th2], and Rorc [Th17]), microRNAs that suppress Tfh generation, and Prdm1 (encoding Blimp-1), which directly suppresses Bcl-6. c-Maf contributes to Tfh cells by inducing CXCR5 and IL-21. STAT3-activating cytokines IL-6, IL-21, and IL-27 can also induce c-Maf, and STAT3 can directly induce IL-21. IL-12 induces IL-21 in a STAT3-dependent manner, but it is unknown whether this involves c-Maf or is a direct effect of STAT3. Tfh generation is restricted by Blimp-1, which is induced by IL-2 in a STAT5-dependent manner and blocks Bcl-6 expression, and by T-bet (induced by IL-12), which physically associates with Bcl-6 and prevents Bcl-6–dependent repression.
Mentions: Bcl-6 functions as a transcriptional repressor. Thus, it was initially difficult to invoke a mechanism by which Bcl-6 actively drives a Tfh program in naive CD4+ T cells. However, several scenarios have now been proposed. As Bcl-6 suppresses GATA3 expression and Th2 responses (Kusam et al., 2003), it could promote Tfh differentiation by interfering with the expression or function of transcription factors that control alternate Th cell fates (Fig. 2). Indeed, enforced expression of Bcl-6 in naive CD4+ T cells cultured under Th1 or Th17 conditions reduces the proportion of IFN-γ− or IL-17–expressing cells (Nurieva et al., 2009; Yu et al., 2009), most likely caused by its ability to bind to consensus sites in the promoters of Tbx21 and Rorc (encoding RORγt), and thus reduce protein expression and/or function. This is consistent with the enhanced generation of Tfh cells from Tbx21-deficient CD4+ T cells both in vivo and in vitro (Nakayamada et al., 2011; Oestreich et al., 2012).

Bottom Line: Ab responses against most antigens (Ags) require interactions between B cells and CD4(+) T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell-dependent B cell responses.Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy.Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.

View Article: PubMed Central - HTML - PubMed

Affiliation: Immunology Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.

ABSTRACT
The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization and clearance of pathogens and subsequent host survival after natural infection with a variety of microorganisms. Most currently available vaccines rely on the induction of long-lived protective humoral immune responses by memory B cells and plasma cells, underscoring the importance of Abs in host protection. Ab responses against most antigens (Ags) require interactions between B cells and CD4(+) T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell-dependent B cell responses. Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.

Show MeSH
Related in: MedlinePlus