Article ; Online: CD4 Effector TCR Avidity for Peptide on APC Determines the Level of Memory Generated.
Journal of immunology (Baltimore, Md. : 1950)
2023 Volume 210, Issue 12, Page(s) 1950–1961
Abstract: Initial TCR affinity for peptide Ag is known to impact the generation of memory; however, its contributions later, when effectors must again recognize Ag at 5-8 d postinfection to become memory, is unclear. We examined whether the effector TCR affinity ... ...
| Abstract | Initial TCR affinity for peptide Ag is known to impact the generation of memory; however, its contributions later, when effectors must again recognize Ag at 5-8 d postinfection to become memory, is unclear. We examined whether the effector TCR affinity for peptide at this "effector checkpoint" dictates the extent of memory and degree of protection against rechallenge. We made an influenza A virus nucleoprotein (NP)-specific TCR transgenic mouse strain, FluNP, and generated NP-peptide variants that are presented by MHC class II to bind to the FluNP TCR over a broad range of avidity. To evaluate the impact of avidity in vivo, we primed naive donor FluNP in influenza A virus-infected host mice, purified donor effectors at the checkpoint, and cotransferred them with the range of peptides pulsed on activated APCs into second uninfected hosts. Higher-avidity peptides yielded higher numbers of FluNP memory cells in spleen and most dramatically in lung and draining lymph nodes and induced better protection against lethal influenza infection. Avidity determined memory cell number, not cytokine profile, and already impacted donor cell number within several days of transfer. We previously found that autocrine IL-2 production at the checkpoint prevents default effector apoptosis and supports memory formation. Here, we find that peptide avidity determines the level of IL-2 produced by these effectors and that IL-2Rα expression by the APCs enhances memory formation, suggesting that transpresentation of IL-2 by APCs further amplifies IL-2 availability. Secondary memory generation was also avidity dependent. We propose that this regulatory pathway selects CD4 effectors of highest affinity to progress to memory. |
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| MeSH term(s) | Mice ; Animals ; CD4-Positive T-Lymphocytes/metabolism ; Interleukin-2/metabolism ; Peptides/metabolism ; Mice, Transgenic ; Receptors, Antigen, T-Cell/metabolism ; Immunologic Memory ; Mice, Inbred C57BL | ||||||||||
| Chemical Substances | Interleukin-2 ; Peptides ; Receptors, Antigen, T-Cell | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2023-10-30 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural | ||||||||||
| ZDB-ID | 3056-9 | ||||||||||
| ISSN | 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381 | ||||||||||
| ISSN (online) | 1550-6606 | ||||||||||
| ISSN | 0022-1767 ; 1048-3233 ; 1047-7381 | ||||||||||
| DOI | 10.4049/jimmunol.2200337 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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