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Loss of Protein Kinase C, Bcl10, or Malt1 Selectively Impairs Proliferation and NF-B Activation in the CD4⁺ T Cell Subset¹

Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814

The cytosolic proteins protein kinase C (PKC), Bcl10, and Malt1 play critical roles in TCR signaling to the transcription factor NF-B. Our data confirm that CD4⁺ T cells from PKC, 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-B activation, whereas NF-B activation is only partially impaired in CD8⁺ T cells. Overall, our results suggest that defects in TCR signaling through PKC, Bcl10, and Malt1 predominantly impair NF-B activation and downstream functional responses of CD4⁺ T cells. In contrast, CD8⁺ T cells maintain substantial NF-B signaling, implying the existence of a significant TCR-regulated NF-B activation pathway in CD8⁺ T cells that is independent of PKC, Bcl10, and Malt1.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Funding for this project was provided by grants to B.C.S. from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (AI057481), the Sidney Kimmel Foundation for Cancer Research, and the Dana Foundation.

² Address correspondence and reprint requests to Dr. Brian C. Schaefer, Department of Microbiology and Immunology, Uniformed Services University, 4301 Jones Bridge Road, Room B3104, Bethesda, MD 20814-4799. E-mail address: bschaefer{at}usuhs.mil

³ Abbreviations used in this paper: PKC, protein kinase C; IKK, IB kinase; WT, wild type; EHAA, Eagle’s Ham’s Amino Acids; PI, propidium iodide; rm, recombinant mouse.