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Nat Immunol
. 2026 Mar 5.
doi: 10.1038/s41590-026-02451-4. Online ahead of print.
Tissue-specific clonal selection and differentiation of CD4⁺ T cells during infection
Roham Parsa 1 2 , Helder C Assis 3 4 , Tiago B R de Castro 5 , Gabriella Lima Dos Reis 3 , Arpita Sushil 6 , Harald Hartweger 7 , Angelina M Bilate 3 , Daniel Mucida 8 9
Affiliations
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.
. 2026 Mar 5.
doi: 10.1038/s41590-026-02451-4. Online ahead of print.
Tissue-specific clonal selection and differentiation of CD4⁺ T cells during infection
Roham Parsa 1 2 , Helder C Assis 3 4 , Tiago B R de Castro 5 , Gabriella Lima Dos Reis 3 , Arpita Sushil 6 , Harald Hartweger 7 , Angelina M Bilate 3 , Daniel Mucida 8 9
Affiliations
- PMID: 41786978
- DOI: 10.1038/s41590-026-02451-4
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.