Developmental bifurcation of human T follicular regulatory cells

Kumar, Saumya; Fonseca, Válter R.; Ribeiro, F. Ramôa; Basto, Afonso P.; Água-Doce, Ana; Monteiro, Marta; Elessa, Dikelele; Miragaia, Ricardo J.; Gomes, Tomás; Piaggio, Eliane; Ségura, Elodie; Gama‐Carvalho, Margarida; Teichmann, Sarah A.; Graça, Luís

doi:10.1126/sciimmunol.abd8411

Cited by 25 publications

(28 citation statements)

References 52 publications

(86 reference statements)

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“…S3A ). The sequenced Treg cells facilitate the identification of bona fide Tfr cells, as we have shown in a recent study with human cells ( 29 ). The assessment of immunoglobulin production confirmed the different types of response: higher IgG1 in OVA/IFA immunization (type-2 response) and predominant IgG2a production with OVA/NP-CpG (type-1 response) ( Fig.…”

Section: Resultsmentioning

confidence: 82%

Specialized Tfh cell subsets driving type-1 and type-2 humoral responses in lymphoid tissue

Kumar

Basto

Ribeiro

et al. 2022

Preprint

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Effective antibody responses are essential to generate protective humoral immunity. Different inflammatory signals polarize T cells towards an appropriate effector phenotype during an infection or immunization. Th1 and Th2 cells have been associated with the polarization of humoral responses for several decades. However, it is now established that T follicular helper cells (Tfh) have a unique ability to access the B cell follicle and support the Germinal Centre (GCs) responses by providing help to B cells. We investigated the specialization of Tfh cells induced under type-1 and type-2 conditions. We first studied homogenous Tfh cell populations generated by adoptively transferred TCR-transgenic T cells in mice immunized with type-1 and type-2 adjuvants. Using a machine learning approach, we established a gene expression signature that discriminates Tfh cells polarized towards type-1 and type-2 response, defined as Tfh1 and Tfh2 cells. The Tfh1 and Tfh2 distinct signature was validated against datasets of Tfh cells induced following LCMV or helminth infection. Using single-cell transcriptomics, we also dissected the heterogeneity of Tfh cells from the two immunizing conditions. Our results show that Tfh cells acquire a specialized function under distinct types of immune responses, but with the coexistence of a small population of Tfh cells of the alternative type. Furthermore, the specific molecular hallmarks of Tfh1 and Tfh2 cells identified herein offer putative new targets for tuning humoral responses.

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Section: Resultsmentioning

confidence: 82%

Specialized Tfh cell subsets driving type-1 and type-2 humoral responses in lymphoid tissue

Kumar

Basto

Ribeiro

et al. 2022

Preprint

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“…To better characterize induced Tfh D3 of different origins, we first analyzed the intensity of CXCR5 expression, which mirrors Tfh cell maturation from non-GC to GC status ( Kumar et al., 2021 ). The lowest CXCR5 mean fluorescence intensity was found in naive-derived Tfh D3 cells, and the highest in Tfh-derived Tfh D3 cells ( Figure 4 A).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, using our experimental design, antigen-experienced PBMCs did not lead to the generation of fully differentiated GC Tfh. Recently published data comparing Tfh isolated from tonsils and from blood showed that independent tissues present distinct proportions of Tfh in different maturation stages ( Kumar et al., 2021 ). Here, our data provide new insights suggesting that the lymphoid environment is required to support the generation of fully differentiated GC Tfh.…”

Section: Discussionmentioning

confidence: 99%

Naive and memory CD4+ T cell subsets can contribute to the generation of human Tfh cells

et al. 2022

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Summary CD4 + T follicular helper cells (Tfh) promote B cell maturation and antibody production in secondary lymphoid organs. By using an innovative culture system based on splenocyte stimulation, we studied the dynamics of naive and memory CD4 + T cells during the generation of a Tfh cell response. We found that both naive and memory CD4 + T cells can acquire phenotypic and functional features of Tfh cells. Moreover, we show here that the transition of memory as well as naive CD4 + T cells into the Tfh cell profile is supported by the expression of pro-Tfh genes, including transcription factors known to orchestrate Tfh cell development. Using this culture system, we provide pieces of evidence that HIV infection differentially alters these newly identified pathways of Tfh cell generation. Such diversity in pathways of Tfh cell generation offers a new framework for the understanding of Tfh cell responses in physiological and pathological contexts.

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“…It has been difficult to compare those studies as the experimental approaches are not directly comparable. For instance, we previously found that circulating Tfr cells have an immature phenotype, given the developmental bifurcation of Tfr cells within human lymphoid tissue 4 , 20 . However, in some studies, Tfr cells are selected within CD45RO + or PD-1 + cells 17 , 21 , excluding a large proportion of this cell population.…”

Section: Introductionmentioning

confidence: 99%

Different antibody-associated autoimmune diseases have distinct patterns of T follicular cell dysregulation

Ribeiro

Romão

Rosa

et al. 2022

Sci Rep

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Autoantibodies are produced within germinal centers (GC), in a process regulated by interactions between B, T follicular helper (Tfh), and T follicular regulatory (Tfr) cells. The GC dysregulation in human autoimmunity has been inferred from circulating cells, albeit with conflicting results due to diverse experimental approaches. We applied a consistent approach to compare circulating Tfr and Tfh subsets in patients with different autoimmune diseases. We recruited 97 participants, including 72 patients with Hashimoto’s thyroiditis (HT, n = 18), rheumatoid arthritis (RA, n = 16), or systemic lupus erythematosus (SLE, n = 32), and 31 matched healthy donors (HD). We found that the frequency of circulating T follicular subsets differed across diseases. Patients with HT had an increased frequency of blood Tfh cells (p = 0.0215) and a reduced Tfr/Tfh ratio (p = 0.0338) when compared with HD. This was not observed in patients with systemic autoimmune rheumatic diseases (RA, SLE), who had a reduction in both Tfh (p = 0.0494 and p = 0.0392, respectively) and Tfr (p = 0.0003 and p = 0.0001, respectively) cells, resulting in an unchanged Tfr/Tfh ratio. Activated PD-1+ICOS+Tfh and CD4+PD-1+CXCR5–Tph cells were raised only in patients with SLE (p = 0.0022 and p = 0.0054), without association with disease activity. Our data suggest that GC dysregulation, assessed by T follicular subsets, is not uniform in human autoimmunity. Specific patterns of dysregulation may become potential biomarkers for disease and patient stratification.

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Developmental bifurcation of human T follicular regulatory cells

Cited by 25 publications

References 52 publications

Specialized Tfh cell subsets driving type-1 and type-2 humoral responses in lymphoid tissue

Specialized Tfh cell subsets driving type-1 and type-2 humoral responses in lymphoid tissue

Naive and memory CD4+ T cell subsets can contribute to the generation of human Tfh cells

Different antibody-associated autoimmune diseases have distinct patterns of T follicular cell dysregulation

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