T cell affinity regulates asymmetric division, effector cell differentiation, and tissue pathology.
The strength of interactions between T cell receptors and the peptide-major histocompatibility complex (pMHC) directly modulates T cell fitness, clonal expansion, and acquisition of effector properties. Here we show that asymmetric T cell division is an important mechanistic link between increased signal strength, effector differentiation, and the ability to induce tissue pathology. Recognition of pMHC above a threshold affinity drove responding T cells into asymmetric cell division. The ensuing proximal daughters underwent extensive division and differentiated into short-lived effector cells expressing the integrin VLA-4, allowing the activated T cell to infiltrate and mediate destruction of peripheral target tissues. In contrast, T cells activated by below-threshold antigens underwent symmetric division, leading to abortive clonal expansion and failure to fully differentiate into tissue-infiltrating effector cells. Antigen affinity and asymmetric division are important factors that regulate fate specification in CD8(+) T cells and predict the potential of a self-reactive T cell to mediate tissue pathology.
Laboratory of Transplantation Immunology, Department of Biomedicine, University Hospital Basel and University of Basel, Switzerland. carolyn.king@unibas.ch
Carolyn G
CG
King
Sabrina
S
Koehli
Barbara
B
Hausmann
Mathias
M
Schmaler
Dietmar
D
Zehn
Ed
E
Palmer
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*
D008024:Ligands; D011948:Receptors, Antigen, T-Cell