Strength of TCR–Peptide/MHC Interactions and In Vivo T Cell Responses

141

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose–response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.

mentioning

confidence: 99%

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Lever

Lim

Krüger

et al. 2016

141

“…The levels of cytokines produced by T cells depend on costimulatory signals, on the affinity, and the amount of antigen (30,31). We stimulated T cells with low (0.1 nM), intermediate (1 nM), and high (100 nM) OVA peptide concentration to determine the effect on cytokine mRNA expression and protein levels.…”

Section: Signal Strength Dictates Protein Production In a Cytokine-spmentioning

confidence: 99%

Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8⁺T cells

Salerno

Paolini

Stark

et al. 2017

127

Effective T cell responses against invading pathogens require the concerted production of three key cytokines: TNF-α, IFN-γ, and IL-2. The cytokines functionally synergize, but their production kinetics widely differ. How the differential timing of expression is regulated remains, however, poorly understood. We compared the relative contribution of transcription, mRNA stability, and translation efficiency on cytokine production in murine effector and memory CD8 + T cells. We show that the immediate and ample production of TNF-α is primarily mediated by translation of preformed mRNA through protein kinase C (PKC)-induced recruitment of mRNA to polyribosomes. Also, the initial production of IFN-γ uses translation of preformed mRNA. However, the magnitude and subsequent expression of IFN-γ, and of IL-2, depends on calcium-induced de novo transcription and PKC-dependent mRNA stabilization. In conclusion, PKC signaling modulates translation efficiency and mRNA stability in a transcript-specific manner. These cytokine-specific regulatory mechanisms guarantee that T cells produce ample amounts of cytokines shortly upon activation and for a limited time.T cells | cytokine production | PKC | mRNA stability | translation efficiency

“…To this end, it is critical to determine what TCR properties correlate to antitumor activity. Substantial evidence indicates a correlation between T-cell functional activity and TCR affinity (12)(13)(14)(15)(16)(17)(18). Subsequently, efforts have been taken to generate modified high-affinity TCRs for clinical studies (19)(20)(21).…”

mentioning

confidence: 99%

T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy

Shi

Malecek

Johnson

et al. 2013

Self Cite

203

215

T cells expressing antigen-specific T-cell receptors (TCRs) can mediate effective tumor regression, but they often also are accompanied by autoimmune responses. To determine the TCR affinity threshold defining the optimal balance between effective antitumor activity and autoimmunity in vivo , we used a unique self-antigen system comprising seven human melanoma gp100(209–217)-specific TCRs spanning physiological affinities (1–100 μM). We found that in vitro and in vivo T-cell responses are determined by TCR affinity, except in one case that was compensated by substantial CD8 involvement. Strikingly, we found that T-cell antitumor activity and autoimmunity are closely coupled but plateau at a defined TCR affinity of 10 µM, likely due to diminished contribution of TCR affinity to avidity above the threshold. Together, these results suggest that a relatively low-affinity threshold is necessary for the immune system to avoid self-damage, given the close relationship between antitumor activity and autoimmunity. The low threshold, in turn, indicates that adoptive T-cell therapy treatment strategies using in vitro-generated high-affinity TCRs do not necessarily improve efficacy.