Reversal of the T cell immune system reveals the molecular basis for T cell lineage fate determination in the thymus

Shinzawa M., Moseman E. A., Gossa S., Mano Y., Bhattacharya A., Guinter T., ...Daha Fazla

NATURE IMMUNOLOGY, cilt.23, sa.5, ss.731-742, 2022 (SCI-Expanded) identifier identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 23 Sayı: 5
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1038/s41590-022-01187-1
  • Dergi Adı: NATURE IMMUNOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.731-742
  • Acıbadem Mehmet Ali Aydınlar Üniversitesi Adresli: Hayır

Özet

To determine how T cell lineage fates are determined in the thymus, Singer and colleagues generated 'FlipFlop' mice with a functionally reversed T cell immune system that distinguishes TCR signal strength versus TCR signal duration. T cell specificity and function are linked during development, as MHC-II-specific TCR signals generate CD4 helper T cells and MHC-I-specific TCR signals generate CD8 cytotoxic T cells, but the basis remains uncertain. We now report that switching coreceptor proteins encoded by Cd4 and Cd8 gene loci functionally reverses the T cell immune system, generating CD4 cytotoxic and CD8 helper T cells. Such functional reversal reveals that coreceptor proteins promote the helper-lineage fate when encoded by Cd4, but promote the cytotoxic-lineage fate when encoded in Cd8-regardless of the coreceptor proteins each locus encodes. Thus, T cell lineage fate is determined by cis-regulatory elements in coreceptor gene loci and is not determined by the coreceptor proteins they encode, invalidating coreceptor signal strength as the basis of lineage fate determination. Moreover, we consider that evolution selected the particular coreceptor proteins that Cd4 and Cd8 gene loci encode to avoid generating functionally reversed T cells because they fail to promote protective immunity against environmental pathogens.