What question did this study set out to answer?

To assess the individual, non-redundant signaling properties of CD3ζ ITAM sequences in CD28-based CARs and determine their effect on CAR T-cell activation, differentiation, and exhaustion.

January 16, 2025Frontiers in ImmunologyOpen Access

The impact of CD3ζ ITAM multiplicity and sequence on CAR T-cell survival and function

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Authors

SMShubhabrata MajumdarBaylor College of Medicine HEHilda EchelibeUniversity of Utah MBMaria BettiniUniversity of Utah

Discussion

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Implication

In vitro experimental study demonstrates calibrated CD3ζ ITAM signaling reduces exhaustion in CAR T-cells, indicating potential to enhance long-term therapeutic persistence.

Key Points

To assess the individual, non-redundant signaling properties of CD3ζ ITAM sequences in CD28-based CARs and determine their effect on CAR T-cell activation, differentiation, and exhaustion.
Engineered second-generation murine anti-CD19 CD28-based CARs with restricted CD3ζ ITAM sequence diversity maintaining a multiplicity of three (designated ζAAA, ζBBB, and ζCCC).
Stimulated CAR T-cells in vitro using CD19+ tumor targets or CD19-coated magnetic beads.
Assessed signaling strength, functional outputs, and phenotype using immunoblotting, flow cytometry-based Ca2+ flux assays, cytotoxicity, degranulation, cytokine secretion, and in vitro exhaustion assays.
ζAAA CARs elicited the strongest signaling magnitude and functional activation profiles, while ζCCC CARs exhibited the weakest activation profile.
Attenuation of signaling in ζCCC CAR T-cells resulted in decreased rates of terminal differentiation, cell exhaustion, and activation-induced cell death compared to ζAAA CARs.

Cite This Study

Majumdar et al. (2025) studied this question.

synapsesocial.com/papers/6a880d2f4c82be800eeb3e29 https://doi.org/10.3389/fimmu.2024.1509980

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Implication

In vitro experimental study demonstrates calibrated CD3ζ ITAM signaling reduces exhaustion in CAR T-cells, indicating potential to enhance long-term therapeutic persistence.

The impact of CD3ζ ITAM multiplicity and sequence on CAR T-cell survival and function

Discussion

Member takes

Implication

Key Points

Cite This Study

The impact of CD3ζ ITAM multiplicity and sequence on CAR T-cell survival and function

Discussion

Member takes

Implication

Key Points

Cite This Study

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