TCR Signal Strength and Antigen Affinity Regulate CD8⁺ Memory T Cells

CD8⁺ T cells play a critical role in adaptive immunity, differentiating into CD8⁺ memory T cells that form the basis of protective cellular immunity. Vaccine efficacy is attributed to long-term protective immunity, and understanding the parameters that regulate development of CD8⁺ T cells is critical to the design of T cell-mediated vaccines. We show in this study using mouse models that two distinct parameters, TCR signal strength (regulated by the tyrosine kinase ITK) and Ag affinity, play important but separate roles in modulating the development of memory CD8⁺ T cells. Unexpectedly, our data reveal that reducing TCR signal strength along with reducing Ag affinity for the TCR leads to enhanced and accelerated development of CD8⁺ memory T cells. Additionally, TCR signal strength is able to regulate CD8⁺ T cell effector cytokine R production independent of TCR Ag affinity. Analysis of RNA-sequencing data reveals that genes for inflammatory cytokines/cytokine receptors are significantly altered upon changes in Ag affinity and TCR signal strength. Furthermore, our findings show that the inflammatory milieu is critical in regulating this TCR signal strength-mediated increase in memory development, as both CpG oligonucleotide treatment or cotransfer of wild-type and Itk T cells eliminates the observed increase in memory cell formation. These findings suggest that TCR signal strength and Ag affinity independently contribute to CD8⁺ memory T cell development, which is modulated by inflammation, and suggest that manipulating TCR signal strength along with Ag affinity, may be used to tune the development of CD8⁺ memory T cells during vaccine development.