T Cell Activation Pathways

Overview

This lecture covers the intracellular signaling pathways activated in T cells after T cell receptor (TCR) engagement, focusing on mechanisms that lead to T cell activation and the importance of co-stimulatory signals.

Goals of T Cell Activation

• T cells recognize pathogen-derived peptides via unique TCRs, requiring peptide-MHC presentation by antigen-presenting cells (APCs).
• TCR (signal 1) and co-stimulatory molecules (signal 2, e.g., CD80) interact at the immune synapse.
• Activated T cells produce effector molecules and cytokines to combat infection.
• CD8⁺ T cells mediate direct cytotoxicity; CD4⁺ T cells provide help via cytokines.

General Principles of Signal Transduction

• Signal pathways start with ligand binding to transmembrane receptors, inducing conformational changes.
• Activation of protein kinases (e.g., Lck, Zap70, PI3K, PKCθ) commonly initiates signaling.
• Scaffold proteins (e.g., LAT) and adapter proteins assemble signaling complexes.
• Small G proteins (e.g., Ras) act as molecular switches, cycling between active (GTP-bound) and inactive (GDP-bound) states.
• Signaling components are concentrated at the plasma membrane via various recruitment strategies.
• Signal amplification occurs through kinase cascades (e.g., MAP kinase) and second messengers (e.g., Ca²⁺).
• Negative regulation involves phosphatases (e.g., calcineurin) and ubiquitination-mediated degradation.

TCR Signal Transduction Pathway

• TCRs contain ITAMs (tyrosine-rich motifs) in their intracellular domains.
• Co-receptor (CD4/CD8) binding brings Lck kinase, which phosphorylates ITAMs on TCR and CD3.
• Phosphorylated ITAMs recruit and activate Zap70, which then phosphorylates LAT and SLP-76.
• Four main signaling modules downstream of Zap70: metabolism (Akt), transcription (PLCγ), cytoskeleton (Vav), and adhesion (ADAP).

PLCγ-Dependent Transcription Factor Activation

• PLCγ hydrolyzes PIP₂ into DAG (membrane-associated) and IP₃ (diffuses in cytosol).
• IP₃ induces Ca²⁺ release, leading to activation of calmodulin, calcineurin, and dephosphorylation/activation of NFAT.
• DAG recruits RasGRP (activates Ras-MAPK cascade → AP-1) and PKCθ (activates NF-κB via degradation of IκB).
• NFAT, AP-1, and NF-κB all converge to drive IL-2 transcription, essential for T cell survival and proliferation.

Role of Co-Stimulation (CD28)

• CD28 on T cells binds CD80/CD86 (B7.1/B7.2) on APCs, providing indispensable co-stimulatory signal.
• CD28 signaling activates PI3K, generating PIP₃, which is necessary for Akt, PLCγ, and Vav activation.
• Co-stimulation optimizes metabolism, cytoskeletal changes, and transcriptional programming in T cells.

Key Terms & Definitions

• TCR (T cell receptor) — recognizes antigenic peptides presented by MHC on APCs.
• APC (Antigen-presenting cell) — cell presenting antigen-MHC complex to TCR.
• ITAM (Immunoreceptor tyrosine-based activation motif) — tyrosine-rich motifs in TCR/CD3 for signal initiation.
• Lck — kinase associated with CD4/CD8, phosphorylates ITAMs.
• Zap70 — tyrosine kinase recruited to phosphorylated ITAMs.
• PLCγ (Phospholipase C gamma) — enzyme generating DAG and IP₃ for downstream signaling.
• NFAT, AP-1, NF-κB — transcription factors critical for T cell activation.
• Co-stimulation (CD28) — second signal from CD80/CD86, crucial for naive T cell activation.

Action Items / Next Steps

• Watch the next lecture (4d) to learn about effector functions mediated by activated T cells.
• Review key signaling pathways and how transcription factors converge on IL-2 gene activation.