Dengue Literature Review

T Cell Responses in Dengue

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T Cell Responses in Dengue

Overview

T cell responses — particularly from CD8+ cytotoxic T lymphocytes (CTLs) — are central to both protective immunity and immunopathology in dengue. The quality, magnitude, and phenotype of T cell responses differ markedly between individuals who develop asymptomatic infection versus dengue fever or dengue hemorrhagic fever. A key unresolved question in dengue immunology is whether pre-existing T cell memory from prior heterologous DENV infection helps or harms during secondary infection (the “original antigenic sin” model predicts cross-reactive T cells may be inefficient against the new serotype yet generate excessive cytokines).

Key T cell populations in dengue:

  • CD8 TEM (effector memory): Primary cytotoxic effectors; can be DENV-specific; marker of clonal expansion
  • CD4 TCM (central memory): Helper coordination; may also acquire cytotoxic function (CD4 CTL)
  • MAIT cells (mucosal-associated invariant T cells): Innate-like; TRAV1-2+ with TRAJ33/TRAJ12/TRAJ20; activated during many viral infections
  • iNKT cells (invariant NKT cells): Innate-like; TRAV10+TRAJ18+ / TRBV25-1+; associated with severe dengue

Key Points from Literature

Asymptomatic dengue — functional CD8 effector response: In asymptomatic dengue, CD8 TEM cells and NK cells are significantly enriched in PBMCs relative to symptomatic cases (P < 0.05), and CD8 TEM cells show the highest degree of clonal expansion (see Sungnak2025 - Distinct Immune Responses Asymptomatic Symptomatic Dengue). The TCR repertoire of expanded CD8 TEM cells is less diverse in asymptomatic donors (higher antigen-driven clonal focus), and expanded clones are predominantly from asymptomatic donors rather than symptomatic ones.

Gene expression profiles of CD8 TEM in asymptomatic dengue are consistent with effective cytotoxic function: high IFNG (IFN-γ), TNF, GZMH (granzyme H), and GNLY (granulysin). This effector profile is proposed to result from enhanced viral antigen presentation via MHC class I — driven by changes in ribosomal protein expression in memory B cells and CD16 monocytes that favour viral peptide generation (RPL6↑, RPS28↑, RPL28↓).

Symptomatic dengue — markers of exhaustion and overactivation: CD8 TEM cells in symptomatic dengue (particularly DHF) express a different profile: PRF1 (perforin) and GZMB (granzyme B) as effector genes, but also markers of dysfunction — FAS (apoptosis), PDCD1 (PD-1), LAG3, and TIGIT (all inhibitory receptors associated with T cell exhaustion and overactivation). Flow cytometry confirmed significantly elevated PD-1 and CD69 surface protein on CD8 T cells in symptomatic dengue, especially DHF.

MAIT and iNKT expansion in severe dengue: MAIT cells (TRAV1-2+) and iNKT cells (TRAV10+TRAJ18+) show significantly higher clonal expansion in DHF compared with DF and AD (P < 0.05). This is consistent with prior literature associating these innate-like T cell subsets with severe dengue. The mechanism may involve bystander activation by dengue-induced cytokines rather than DENV-specific TCR recognition.

CD4 CTLs: Also observed to be clonally expanded (consistent with prior reports of dengue-specific CD4 cytotoxic T lymphocytes). CD4 proliferating T cells in DHF show the highest IL10 expression and are proposed (via CellChat analysis) to signal to plasmablasts through IL-10/IL-10R — potentially driving pathogenic plasma cell expansion.

Longitudinal dynamics: From febrile phase to 2-month convalescence, proliferating T cells contract. However, CD8-proliferating T cells from the febrile phase were found to transition to CD8 TEM identity at convalescence in 5/6 donors, suggesting the effector-to-memory transition occurs partly from this proliferating pool rather than exclusively from pre-existing CD8 TEM.

T cell biology from Guzman2016

Guzman2016 provides a review-level summary of T cell knowledge as of 2016 (see Guzman2016 - Dengue Infection):

  • The relative contribution of antibody-mediated vs T cell–mediated immunity to dengue protection is not well understood — both are recognised as important
  • CD8+ T cells: effective CD8+ CTL immunity is largely directed against NS protein epitopes (not E protein, which is the predominant vaccine antigen in live attenuated vaccines using only prM/E); NS-specific CD8 T cells contribute to viral clearance but may also produce immunopathological cytokines in secondary heterotypic infection (original antigenic sin model; see Original Antigenic Sin)
  • CD4+ T cells contribute to protection through multiple mechanisms:
    1. Antiviral cytokine production (IFN-γ, TNF-α)
    2. Cytotoxic killing of DENV-infected cells (CD4 CTL)
    3. Enhancement of CD8 T cell responses (T helper function)
    4. Enhancement of B cell and antibody responses (follicular helper T cell function)
    5. Promotion of immune memory formation
  • Cross-reactive T cells from a prior heterologous infection are re-expanded preferentially in secondary dengue — the mechanistic basis for OAS; whether this is net protective or pathological remains debated
  • Vaccine implication: vaccines that include NS protein antigens (TV003/TV005 live attenuated; some DNA vaccines) may induce more protective CD8 T cell responses than vaccines relying solely on E protein (CYD-TDV, subunit DEN-80E, inactivated DPIV) — a prediction now supported by Sungnak2025’s finding that NS-epitope CD8 TEM functional profiles characterise asymptomatic/protective immunity

Contradictions & Debates

The relative importance of antibody-mediated (ADE) versus T cell–mediated immunopathology in severe dengue remains debated. Sungnak2025 identifies transcriptomic evidence for both, but the two mechanisms may cooperate: ADE-mediated entry could increase intracellular viral antigen load, driving excessive T cell activation. The “original antigenic sin” model predicts that cross-reactive, low-avidity T cells from prior heterologous infection dominate the response and produce excessive cytokines (e.g., TNF, IFN-γ) without efficiently killing infected cells — but Sungnak2025’s data show the highest effector gene expression (including IFNG, TNF) in asymptomatic donors, which complicates the simple model that high cytokine production = pathology.

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