Allergen-specific IgG+ memory B cells are temporally linked to IgE memory responses

BACKGROUND: Immunoglobulin E (IgE) are least abundant, tightly regulated and IgE producing B cells are rare. The cellular origin and evolution of IgE responses are poorly understood. OBJECTIVE: To investigate the cellular and clonal origin of IgE memory responses following mucosal allergen exposure by sublingual immunotherapy (SLIT). METHODS: In a randomized double-blind, placebo-controlled, time-course SLIT study, peripheral blood mononuclear cells (PBMCs) and nasal biopsies were collected from forty adults with seasonal allergic rhinitis at baseline, 4, 8, 16, 28 and 52 weeks. RNA was extracted from PBMCs, sorted B cells and nasal biopsies for VH repertoire sequencing. Moreover, monoclonal antibodies were derived from single B cell transcriptomes. RESULTS: Combining VH repertoire sequencing and single cell transcriptomics yielded direct evidence of a parallel boost of two clonally and functionally related B cell subsets of short-lived IgE+ plasmablasts and IgG+ memory B cells (termed IgGE). Mucosal grass pollen allergen exposure by SLIT resulted in highly diverse IgE and IgGE repertoires. These were extensively mutated and appeared relative stable as per heavy chain isotype, somatic hypermutations and clonal composition. Single IgGE + memory B cell and IgE+ pre-plasmablast transcriptomes encoded antibodies that were specific for major grass pollen allergens and were able to elicit basophil activation at very low allergen concentrations. CONCLUSION: For the first time, we have shown that upon mucosal allergen exposure, human IgE memory resides in allergen-specific IgG+ memory B cells. These rapidly switch isotype and expand into short-lived IgE+ plasmablasts and serve as a potential target for therapeutic intervention

CD4⁺ follicular helper-like T cells are key players in anti-tumor immunity

ABSTRACT To determine the nature of CD4 + T cells that provide ‘help’ for generating robust anti-tumor CD8 + cytotoxic T cell (CTL) responses, we profiled the transcriptomes of patient-matched CD4 + and CD8 + T cells present in the tumor micro-environment (TME) and analyzed them jointly using integrated weighted gene correlation network analysis. We found the follicular helper T cell (T FH ) program in CD4 + T cells was strongly associated with proliferation and tissue-residency in CD8 + CTLs. Single-cell analysis demonstrated the presence of T FH -like cells and features linked to cytotoxic function and their provision of CD8 + T cell ‘help’. Tumor-infiltrating T FH -like cells expressed PD-1 and were enriched in tumors following checkpoint blockade, suggesting that they may respond to anti-PD-1 therapy. Adoptive transfer or induction of T FH cells in mouse models resulted in augmented CD8 + CTL responses and impairment of tumor growth, indicating an important role of T FH -like CD4 + T cells in anti-tumor immunity