Loss of protein kinase Cθ, Bcl10, or Malt1 selectively impairs proliferation and NF-κB activation in the CD4⁺ T cell subset

The cytosolic proteins protein kinase Cθ (PKCθ), Bcl10, and Malt1 play critical roles in TCR signaling to the transcription factor NF-κB. Our data confirm that CD4⁺ T cells from PKCθ, Bcl10, and Malt1 knockout mice show severe impairment of proliferation in response to TCR stimulation. Unexpectedly, we find that knockout CD8⁺ T cells proliferate to a similar extent as wild-type cells in response to strong TCR signals, although a survival defect prevents their accumulation. Both CD4⁺ and CD8⁺ knockout T cells express activation markers, including CD25, following TCR stimulation. Addition of exogenous IL-2 rescues survival of knockout CD4⁺ and CD8⁺ T cells, but fails to overcome the proliferation defect of CD4⁺ T cells. CD4 ⁺ T cells from knockout mice are extremely deficient in TCR-induced NF-κB activation, whereas NF-κB activation is only partially impaired in CD8⁺ T cells. Overall, our results suggest that defects in TCR signaling through PKCθ, Bcl10, and Malt1 predominantly impair NF-κB activation and downstream functional responses of CD4⁺ T cells. In contrast, CD8⁺ T cells maintain substantial NF-κB signaling, implying the existence of a significant TCR-regulated NF-κB activation pathway in CD8⁺ T cells that is independent of PKCθ, Bcl10, and Malt1.