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Helper T cell immunity in humans with inherited CD4 deficiency.

ABSTRACT: CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαβ+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αβ T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.

SUBMITTER: Guerin A

PROVIDER: S-EPMC10983808 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature

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Helper T cell immunity in humans with inherited CD4 deficiency.

Guérin Antoine A Moncada-Vélez Marcela M Jackson Katherine K Ogishi Masato M Rosain Jérémie J Mancini Mathieu M Langlais David D Nunez Andrea A Webster Samantha S Goyette Jesse J Khan Taushif T Marr Nico N Avery Danielle T DT Rao Geetha G Waterboer Tim T Michels Birgitta B Neves Esmeralda E Iracema Morais Cátia C London Jonathan J Mestrallet Stéphanie S Quartier Dit Maire Pierre P Neven Bénédicte B Rapaport Franck F Seeleuthner Yoann Y Lev Atar A Simon Amos J AJ Montoya Jorge J Barel Ortal O Gómez-Rodríguez Julio J Orrego Julio C JC L'Honneur Anne-Sophie AS Soudée Camille C Rojas Jessica J Velez Alejandra C AC Sereti Irini I Terrier Benjamin B Marin Nancy N García Luis F LF Abel Laurent L Boisson-Dupuis Stéphanie S Reis Joel J Marinho Antonio A Lisco Andrea A Faria Emilia E Goodnow Christopher C CC Vasconcelos Julia J Béziat Vivien V Ma Cindy S CS Somech Raz R Casanova Jean-Laurent JL Bustamante Jacinta J Franco Jose Luis JL Tangye Stuart G SG

The Journal of experimental medicine 20240401 5

CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HL ...[more]

PMID: 38557723

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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

Helper T cell immunity in humans with inherited CD4 deficiency.

Publications

Helper T cell immunity in humans with inherited CD4 deficiency.

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