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<p>Pathogen-specific CD4⁺ T cells expand and contract during infection, generating memory clones that shape subsequent immune responses. How distinct tissue environments influence differentiation and clonal selection of polyclonal T cells remains unclear. Here we develop Tracking Recently Activated Cell Kinetics (TRACK) mice, a dual-recombinase fate-mapping system enabling the spatial and temporal labeling of recently activated CD4⁺ T cells. Using TRACK mice during influenza infection, we observed organ-specific transcriptional differentiation and clonal selection in lung, mediastinal lymph nodes (medLNs) and spleen. During the effector phase, spleen-derived CD4⁺ T cells adopted a stem-like migratory phenotype, whereas medLN-activated cells differentiated into T follicular helper cells. T cell receptor sequencing showed low clonal overlap between tissues during the effector response, consistent with distinct antigenic landscapes. During memory formation, overlap increased between lung- and medLN-derived cells, while splenic clones retained a distinct repertoire. These findings define tissue-dependent mechanisms that shape CD4⁺ T cell fate and clonal architecture.</p>

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Tissue-specific clonal selection and differentiation of CD4⁺ T cells during infection

  • 期刊论文

  • 发表日期：

    2026年3月5日

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  • Roham Parsa,
  • Helder C. Assis,
  • Tiago B. R. de Castro,
  • Gabriella Lima dos Reis,
  • Arpita Sushil,
  • Harald Hartweger,
  • Angelina M. Bilate,
  • Daniel Mucida

摘要

Pathogen-specific CD4⁺ T cells expand and contract during infection, generating memory clones that shape subsequent immune responses. How distinct tissue environments influence differentiation and clonal selection of polyclonal T cells remains unclear. Here we develop Tracking Recently Activated Cell Kinetics (TRACK) mice, a dual-recombinase fate-mapping system enabling the spatial and temporal labeling of recently activated CD4⁺ T cells. Using TRACK mice during influenza infection, we observed organ-specific transcriptional differentiation and clonal selection in lung, mediastinal lymph nodes (medLNs) and spleen. During the effector phase, spleen-derived CD4⁺ T cells adopted a stem-like migratory phenotype, whereas medLN-activated cells differentiated into T follicular helper cells. T cell receptor sequencing showed low clonal overlap between tissues during the effector response, consistent with distinct antigenic landscapes. During memory formation, overlap increased between lung- and medLN-derived cells, while splenic clones retained a distinct repertoire. These findings define tissue-dependent mechanisms that shape CD4⁺ T cell fate and clonal architecture.