Dataset Information

MiR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation.

ABSTRACT: Follicular helper T (TFH) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating TFH cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated TFH cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced TFH cell responses. Mechanistically, miR-23~27~24 clusters coordinately control TFH cells through targeting a network of genes that are crucial for TFH cell biology. Among them, thymocyte selection-associated HMG-box protein (TOX) was identified as a central transcription regulator in TFH cell development. TOX is highly up-regulated in both mouse and human TFH cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in TFH cell differentiation and function. Collectively, our results establish a key miRNA regulon that maintains optimal TFH cell responses for resultant humoral immunity.

SUBMITTER: Wu CJ

PROVIDER: S-EPMC6905868 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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MiR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation.

Wu Cheng-Jang CJ Cho Sunglim S Huang Hsi-Yuan HY Lu Chun-Hao CH Russ Jasmin J Cruz Leilani O LO da Cunha Flavia Franco FF Chen Mei-Chi MC Lin Ling-Li LL Warner Lindsey M LM Liao Hsin-Kai HK Utzschneider Daniel T DT Quon Sara S Berner Jacqueline J Camara Niels Olsen Saraiva NOS Zehn Dietmar D Belmonte Juan Carlos Izpisua JCI Chen Li-Chen LC Huang Shiang-Fu SF Kuo Ming-Ling ML Lu Li-Fan LF

Science advances 20191211 12

Follicular helper T (TFH) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating TFH cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated TFH cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced TFH cell responses. Mechanistically, miR-23~27~24 clusters coordinately contr ...[more]

PMID: 31844658

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Project description:During activation, the T cell transmembrane receptor CD6 becomes incorporated into the T cell immunological synapse where it can exert both co-stimulatory and co-inhibitory functions. Given the ability of CD6 to carry out opposing functions, this study sought to determine how CD6 regulates early T cell activation in response to viral infection. Infection of CD6-deficient mice with a neurotropic murine coronavirus resulted in greater activation and expansion of CD4 T cells in the draining lymph nodes. Further analysis demonstrated that there was also preferential differentiation of CD4 T cells into T follicular helper cells, resulting in accelerated germinal center responses and emergence of high-affinity virus-specific antibodies. Given that CD6 conversely supports CD4 T cell activation in many autoimmune models, we probed potential mechanisms of CD6-mediated suppression of CD4 T cell activation during viral infection. Analysis of CD6 binding proteins revealed that infection-induced upregulation of Ubash3a, a negative regulator of T cell receptor (TCR) signaling, was hindered in CD6-deficient lymph nodes. Consistent with greater T cell activation and reduced UBASH3a activity, the T cell receptor signal strength was intensified in CD6-deficient CD4 T cells. These results reveal a novel immunoregulatory role for CD6 in limiting CD4 T cell activation and deterring CD4 T follicular helper cell differentiation, thereby attenuating antiviral humoral immunity.ImportanceCD6 monoclonal blocking antibodies are being therapeutically administered to inhibit T cell activation in autoimmune disorders. However, the multifaceted nature of CD6 allows for multiple and even opposing functions under different circumstances of T cell activation. We therefore sought to characterize how CD6 regulates T cell activation in the context of viral infections using an in vivo murine coronavirus model. In contrast to its role in autoimmunity, but consistent with its function in the presence of superantigens, we found that CD6 deficiency enhances CD4 T cell activation and CD4 T cell help to germinal center-dependent antiviral humoral responses. Finally, we provide evidence that CD6 regulates transcription of its intracellular binding partner UBASH3a, which suppresses T cell receptor (TCR) signaling and consequently T cell activation. These findings highlight the context-dependent flexibility of CD6 in regulating in vivo adaptive immune responses, which may be targeted to enhance antiviral immunity.

Dataset Information

MiR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation.

Publications

MiR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation.

Similar Datasets

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