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Open research questions in T-cell and B-cell Immunology

75 unresolved questions extracted from the limitations and future-work sections of 319 T-cell and B-cell Immunology papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • How naive CD8+ T cells develop into memory T cells that bifurcate into long-lived central (TCM) versus effector (TEM) subsets after an antigen encounter remains ill-defined at the molecular level.

    Atomistic TCR-ligand interactions instruct memory T-cell differentiation 2330211 · 2026 · DOI

  • While the somatic diversification of TCRs has been extensively studied, inherited genetic diversity in the TCR V, D, and J genes has remained poorly characterized due to the complex, repetitive nature of the TCR loci.

    TCR germline diversity reveals evidence of natural selection on variable and joining alpha chain genes 2250859 · 2026 · DOI

  • Abstract Introduction Commonly used to treat inflammatory skin diseases, narrowband ultraviolet B (UVB) has been shown to induce antigen-specific immune suppression when combined with alloantigen immunization, but the underlying mechanism remains elusive.

    Narrowband ultraviolet B induces peripheral regulatory T cells to exert antigen-specific immune suppression 2308173 · 2026 · DOI

  • Abstract Introduction The adaptor protein SLP-76 is indispensable for thymic T-cell development, yet its contribution to peripheral T-cell signaling and metabolic programming remains poorly defined.

    Adaptor SLP-76 couples the TCR to glucose metabolism in T-cells with augmented obesity 2310033 · 2026 · DOI

  • Epitope spreading has long been proposed as a mechanism contributing to the progression of multiple sclerosis (MS), yet its role in human disease remains incompletely defined.

    Epitope spreading in multiple sclerosis is shaped by the spatial organisation of immune responses · 2026 · DOI

  • Both the mechanisms controlling EF MBC differentiation and the identities of the B cell populations from which EF MBCs derive remain poorly understood.

    A Germinal Center-Independent Innate-Like Memory B Cell Compartment of B1 Origin · 2026 · DOI

  • Notably, AREG alone was insufficient to induce this effect, highlighting its role as a context-dependent amplifier of inflammation specifically in TNF -enriched inflamed tissues.

    Functional and dysfunctional T regulatory cell states in human tissues in RA and other autoimmune arthritic diseases · 2026 · DOI

  • The discovery of epidermal TRM cells has fundamentally ad- vanced our understanding of human skin immunity. Accumulating evidence indicates that the epidermis harbors specialized popula- tions of conventional and regulatory TRM cells that cooperate with LCs and keratinocytes to maintain local immune homeostasis. Future studies integrating spatial biology, single-cell technologies, and in situ imaging will further elucidate how this epidermal immune network is organized in health and disrupted in disease (57). Such insights may facilitate the development of novel thera- peutic strategies for epidermis-centered inflammatory, infectious, and neoplastic disorders.

    Human epidermal resident memory T cells: beyond the dermal perspective · 2026 · DOI

  • Biological sex can profoundly influence the susceptibility to infectious diseases, yet the mechanisms behind the sex-dependent protective immunity against tuberculosis (TB) remain poorly understood.

    Intrinsic T-cell programming and immune spatial organization govern sex-biased tuberculosis immunity · 2026 · DOI

  • Immune effector cell-associated neurotoxicity syndrome (ICANS) is a major complication after CAR T cell therapy, but its underlying mechanisms remain poorly understood.

    Coordinated expansion of CD163⁺ monocytes and immature CD177⁺ neutrophils marks severe neurotoxicity after CD19 CAR T cell therapy · 2026 · DOI

  • Virtual memory T cells are increasingly recognized as a functionally distinct lineage within the CD8 T cell pool, but when and how commitment to the lineage is enforced remain poorly understood.

    Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fate · 2026 · DOI

  • Segmented filamentous bacteria (SFB) are a canonical model of microbiota-driven Th17 immunity, but how distinct gut-associated lymphoid tissues shape the quality and effector potential of commensal-specific T-cell responses remains unclear.

    LysoDCs in Peyer's patches program compartmentalized microbiota-specific Th17 responses · 2026 · DOI

  • Lack of evidence for involvement of fetal microchimerism in pathogenesis of primary biliary cirrhosis. Lack of evidence of foetal microchimerism in female Spanish patients with systemic sclerosis. Lack of evidence for an increased microchimerism in the circulation of patients with Sjögren's syndrome.

    Microchimerism: The Hidden Cellular Dialogue Between Mother and Fetal That Shapes Lifelong Immunity · 2026 · DOI

  • Aging induces immunosenescence, a progressive decline in immune function underpinning age-related pathogen vulnerability, yet T/B cell receptor (TCR/BCR) repertoire remodeling during aging remains incompletely characterized, especially in non-European populations.

    An Aging Clock Based on Immune Repertoire Features: <scp>COVID</scp> ‐19 Accelerates Aging · 2026 · DOI

  • (cid:129) Dose requirements (cid:129) Persistence (cid:129) Potency (cid:129) Variability (cid:129) Antigen identification (cid:129) HLA restriction (cid:129) Epitope…

    Regulatory T cells: master orchestrators of immune tolerance and tissue homeostasis · 2026 · DOI

  • Long-standing paradigms are being progressively challenged, and PC heterogeneity, which has long gone unnoticed due to the technical limitations imposed by their scarcity, has now emerged as an undeniable yet poorly understood feature.

    Not all plasma cells are made equal: well-hidden layers of heterogeneity · 2026 · DOI

  • Tissue-resident memory (TRM) T-cells are increasingly recognized as key mediators of chronic autoimmune inflammation, yet their organization and functional adaptation within the eye remain poorly understood.

    Distinct Programs of Tissue Adaptation Shape Vitreous CD4+ and CD8+ T-cell States in Chronic Uveitis · 2026 · DOI

  • These data support further investigation of the Tex-KLR subtype and its role, dynamics, and targetable translational applications to cancer immunotherapy.

    High-avidity TCR signaling induces a distinct KLR-positive exhaustion state in human tumor-infiltrating CD8 T cells associated with immunotherapy response · 2026 · DOI

  • TregFD retained a near-wild-type transcriptome (differential expression limited to adhesion pathways), yet failed to suppress autoimmunity or DC-driven T cell proliferation.

    Hierarchical Immune Suppressive Functions of Regulatory T Cells Built on Mechanical Force · 2026 · DOI

  • Several limitations of this study should be acknowledged. First, the sample size is relatively small, which may limit statistical power and generalizability. Validation in larger independent cohorts is necessary to confirm the robustness and broader applicability of our findings. Second, this study employed a cross-sectional design, capturing the transcriptomic landscape of peripheral blood mononuclear cells at a single time point. Residual confounding by unmeasured factors such as subclinical differences in disease activity cannot be entirely excluded. The differences identified between RF+ and RF- groups represent correlative findings that require prospective validation. Third, several key analyses in this study are fundamentally computational in nature. Pseudo-time trajectory analysis reconstructs putative differentiation states based on transcriptomic similarity across simultaneously captured cells and does not constitute direct temporal observation of cellular differentiation processes; the inferred trajectories should therefore be regarded as hypothesis-generating predictions rather than confirmed differentiation pathways. Similarly, cell–cell communication results derived from CellChat are computational predictions based on known ligand–receptor interaction databases and gene expression levels, and do not represent experimentally verified signaling events.

    Immunological profiling of rheumatoid factor-positive primary Sjögren’s syndrome by single-cell RNA sequencing · 2026 · DOI

  • Funding Integrated summary: the special position of gd T cells in immunological strategy gd T cells stand apart from the conventional ab lineage because they operate independently of MHC constraints and directly recognize stress or malignant signals (288–290). This independence grants them the quality of immediate response and the vigor of innate defense, while also bearing adaptive potential. Their distri- bution is not uniform: Vd1+ gd T cells guard the mucosa and epithelial outposts of the body, whereas circulating Vg9Vd2+ gd T cells prove powerful against hematologic malignancies (118, 291, 292). In practice, clinical evidence has shown that in ALL and AML, infiltration by these cells correlates with improved survival (293–295). Translational vision: broadening application from laboratory insight Antigens such as CD123 become vulnerable to gd T cell targeting even when tumor HLA-I is lost (296–298). Clinical studies suggest that patients with post-transplant gd T-cell recovery >10% may have improved survival outcomes after transplant attain superior survival-proof of their graft-versus-leukemia role (299– 301). In alliance with chemotherapy, radiotherapy, or checkpoint blockade, their effect is magnified (302–304). Further, bispecific antibodies and lymphodepletion schemes may rouse their force in refractory AML or CLL (305–307). Beyond malignancy, they can aid repair in aplastic anemia, though under other conditions they may intensify autoimmunity, as in hemolytic anemia (307–310). Thus, to distinguish subsets with single-cell sequencing is the path to stratified and precise application (311–313).

    Translational potential of γδ T cells in hematologic diseases: from immunobiology to therapeutic innovation · 2026 · DOI

  • Abstract Although acute rejection threatens allograft function, little is known about the functional properties of graft-specific effector CD8+ T cells.

    CD8+ T Cells Differentiate into a Potent CD43+ Effector Population During Acute Allograft Rejection · 2023 · DOI

  • The E3 ubiquitin ligase Itch prevents the emergence of autoimmune disease and autoantibodies in humans and mice, and patients lacking Itch develop debilitating, multi-faceted, potentially fatal, autoimmune disease; yet how Itch regulates GC B cell fate or function is not well understood.

    The ubiquitin ligase Itch skews light zone selection in germinal centers · 2023 · DOI

  • <ns3:p> <ns3:bold>Background:</ns3:bold> The characterisation of the peripheral immune system in the autoimmune disease systemic lupus erythematosus (SLE) at the single-cell level has been limited by the reduced sensitivity of current whole-transcriptomic technologies.

    Single-cell multi-omics analysis reveals IFN-driven alterations in T lymphocytes and natural killer cells in systemic lupus erythematosus · 2021 · DOI

  • The manuscript describes that positive selection in double-positive thymocytes involves recognition of self-peptide-HLA complexes with low affinity interactions, but the quantitative affinity thresholds distinguishing positive selection signals from negative selection across different self-peptide-HLA combinations have not been systematically established.

    Cell Biology of the Immune System · 2021 · DOI

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75 open questions have been extracted from the limitations and future-work passages of 319 T-cell and B-cell Immunology papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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