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

What the literature leaves open

• Further studies on the impact of COVID-19 on immune repertoire aging are needed, - Investigations into the clinical applications of the immune repertoire aging clock are required, - Research on the effects of COVID-19 on immune function in different populations is necessary

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

• Formulating precision immunomodulatory strategies tailored to specific time windows and cell subsets, - Investigating the role of unconventional T cells in various tissue injury patterns, - Examining the dual functions of unconventional T cells in IRI, - Elucidating the mechanisms of context-dependent immunomodulation by unconventional T cells

  Multifaceted mechanisms of unconventional T cells in ischemia-reperfusion injury · 2026 · DOI

• The potential functional impact of Thy1 expression on T cell differentiation. The need to distinguish donor T cells from the endogenous host population. The challenge of developing a reliable and versatile platform for CD8+ T cell differentiation studies.

  Thy1 retroviral reporters: a versatile platform for congenic background-independent adoptive transfer and CD8+ T cell differentiation studies · 2026 · DOI

• The need for labor-intensive construction of specific congenic mouse strains for adoptive T cell transfer. The lack of a reliable surface reporter for monitoring adoptively transferred CD8+ T cell differentiation.

  Thy1 retroviral reporters: a versatile platform for congenic background-independent adoptive transfer and CD8+ T cell differentiation studies · 2026 · DOI

• The short half-life of wildtype IL-2 limits its therapeutic potential. The activation of non-Treg immune cells, such as Tconv, γδ T cells, and NK cells, is a challenge for IL-2-based therapies. The need to enhance Treg selectivity while maintaining full suppressive activity is a technical challenge.

  IL-2 mutein selectively expands thymic memory Tregs with increased transendocytosis activity in healthy participants · 2026 · DOI

• Further study is needed to determine the effects of MK-6194 on Treg function and immune tolerance in patients with autoimmune and inflammatory disorders, - Research is needed to examine the potential utility of combining MK-6194 with other therapies to enhance Treg selectivity, - Studies should investigate the effects of MK-6194 on Treg heterogeneity and function in vivo

  IL-2 mutein selectively expands thymic memory Tregs with increased transendocytosis activity in healthy participants · 2026 · DOI

• The in vitro model of human T reg cell instability is yet to be tested in vivo - The study only investigated the effects of inflammatory cytokines on human T reg cell lineage stability in vitro

  Deletion of a distal IRF4 element prevents inflammation-induced reprogramming of human regulatory T cell fate · 2026 · DOI

• Tracking T reg cell TCR clonotypes and epigenome over time in autoimmune versus normal controls - Investigating the molecular signatures of human T reg cell lineage decommitment

  Deletion of a distal IRF4 element prevents inflammation-induced reprogramming of human regulatory T cell fate · 2026 · DOI

• Germinal center (GC) B cells undergo extensive apoptosis, but how this process shapes evolving GC populations remains unclear.

  Apoptotic Quality Control of Cellular Competence Limits Cryptic Germinal Center B Cell States · 2026 · DOI

• However, the precise molecular immune responses, particularly involving T-cell receptor (TCR) repertoire changes after full vaccination, and the use of TCR analysis to evaluate vaccine efficacy, remain incompletely understood.

  An Artificial Intelligence Model for Longitudinal Assessment of TCR Repertoires in SARS-CoV-2 Vaccine Recipients · 2026 · DOI

• Neurodegenerative diseases are increasingly recognized to involve detrimental interactions between the immune and nervous systems, yet whether failure of peripheral immune tolerance actively drives neuronal loss frequently remains unclear.

  Impaired regulatory T cell mediated immune tolerance promotes neurodegeneration in glaucoma · 2026 · DOI

• Nomenclature is always imperfect, but a rethinking of current B cell nomenclature is warranted.

  Extrafollicular and other non-germinal center B cell responses · 2026 · DOI

• T cell immunity depends on the precise coordination of signaling networks with actin cytoskeleton remodeling, yet the molecular regulators of these processes remain incompletely defined.

  Loss of the actin remodeling protein Flightless-1 impairs CD8 and regulatory T cell function · 2026 · DOI

• However, the mechanisms behind ABC generation and maintenance remain poorly understood.

  Critical roles of chronic BCR signaling in the differentiation of anergic B cells into age-associated B cells in aging and autoimmunity · 2025 · DOI

• However, pioneering studies have shown an anti-inflammation role for OGG1 in inflammatory bowel disease (IBD), but its underlying molecular mechanism remains unclear.

  OGG1 augments the transcriptional activation of Foxp3 to promote iTreg differentiation for IBD alleviation · 2025 · DOI

• Tissue resident memory T cells (TRM) provide protection against local re-infection, and yet the interstitial signals that govern their formation and persistence remain poorly defined.

  CXCR6 promotes dermal CD8+ T cell survival and transition to long-term tissue residence · 2025 · DOI

• Tissue-resident memory cells contribute to allergen-induced inflammation and airway hyperresponsiveness, but relatively little is known of the cellular and molecular mechanisms underlying the accumulation of these cells in the lung.

  Lung-resident memory CD4+ T cells are dependent on Batf3 · 2025 · DOI

• The mechanisms controlling the inclusion of new B cell clones into spontaneous germinal centers (GCs) remain unclear.

  Dynamic control of autoreactive B cells from spontaneous germinal centers · 2025 · DOI

• While the cell-intrinsic and -extrinsic signals responsible for regulating BM PC function have been extensively studied, these regulatory signals are understudied in gut PCs.

  Restriction of IgA secretion in gut plasma cells is driven by a tissue-specific glycolytic program · 2025 · DOI

• However, the way in which different TCR signal strengths and other auxiliary signals coordinate downstream of the γδ TCR to regulate γδ T-cell development remains unclear.

  RasGRP1 signaling is required for Vγ2+ thymocyte c-Maf expression and γδT17 lineage programming · 2025 · DOI

• Nevertheless, the full impact of MARCH1 and the ubiquitin-dependent MHCII turnover on the development, activation, and functions of B cells remains to be explored.

  Ubiquitination of MHC class II molecules regulates B-cell development and response to antigens in mice · 2025 · DOI

• The retinoic acid receptor-related orphan receptor alpha (RORα), a member of the nuclear receptor family of ligand-regulated transcription factors, has emerged as a potential transcriptional regulator of CD8+ T cell immunity, though its role in these processes remains poorly understood.

  RORα regulates the differential development of CD8+ memory subsets 4623 · 2025 · DOI

• While the role of antigen affinity on T cell activation and T cell Receptor (TCR) signaling has been well studied, the impact on trogocytosis efficiency and subsequent trogocytosis-mediated signaling remains unknown.

  Trogocytosis efficiency and trogocytosis-mediated signaling correlates with TCR affinity for MHC: peptide ligands 2579 · 2025 · DOI

• New naïve B cell are produced in the bone marrow of elderly individuals, but changes in naïve B cell generation with age are poorly characterized.

  Age-related BCR heavy chain repertoire changes in young and older adults tracked for a decade 9178 · 2025 · DOI

• The encoding of memory and control of rapid recall across lifespan is poorly understood, yet the mechanisms are fundamental to pathogen defense and inflammatory diseases.

  Gene regulatory network determinants of rapid recall in human memory T cells 3929 · 2025 · DOI

Most-cited papers in T-cell and B-cell Immunology

• Control of Regulatory T Cell Development by the Transcription Factor Foxp3 · Science · 2003 · 6,624 citations
• Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells · Nature · 2006 · 5,749 citations
• Two subsets of memory T lymphocytes with distinct homing potentials and effector functions · Nature · 1999 · 4,733 citations
• Restoring function in exhausted CD8 T cells during chronic viral infection · Nature · 2005 · 3,390 citations
• Functional diversity of helper T lymphocytes · Nature · 1996 · 3,208 citations
• Phenotypic Analysis of Antigen-Specific T Lymphocytes · Science · 1996 · 2,746 citations
• A CD4+T-cell subset inhibits antigen-specific T-cell responses and prevents colitis · Nature · 1997 · 2,677 citations
• CTLA-4 Control over Foxp3 + Regulatory T Cell Function · Science · 2008 · 2,590 citations
• The Immunological Synapse: A Molecular Machine Controlling T Cell Activation · Science · 1999 · 2,519 citations
• B cells and tertiary lymphoid structures promote immunotherapy response · Nature · 2020 · 2,477 citations

Most recent work

• Next steps in regulatory T cells: Biology and clinical application · Cell · 2026
• Immune signatures of common exposures through co-occurrence of T-cell receptors in tens of thousands of donors · bioRxiv · 2026
• The TCR and LCK: foundations for T-cell activation and therapeutic innovation · Frontiers in Immunology · 2026
• Sympathetic-epithelial crosstalk governs tissue-resident memory T cell immunosurveillance in the skin · Cell · 2026
• Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer · Cell · 2026
• The αβTCR repertoire at scale in the immgenT dataset · bioRxiv · 2026
• Regulatory T cells: master orchestrators of immune tolerance and tissue homeostasis · Frontiers in Science · 2026
• Characterization of bronchovascular-bundle mesenchymal stromal cells regulating antibody-secreting cell niche in rejecting lung allografts · bioRxiv · 2026
• A Germinal Center Checkpoint of AIRE in B Cells Limits Antibody Diversification · bioRxiv · 2026
• CD24 and CD27 resolve ontogeny and gradual differentiation of CD11c+ atypical memory B cells after malaria infection · bioRxiv · 2026

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