Lecture 15_T cell activation & CD4T cell differentiation_FA24

Phases of T Lymphocyte Development

Overview of Phases

  • Phase I: Generation of antigen receptor (TCR)

  • Phase II: Refinement of TCR repertoire in the thymus

  • Phase III: Activation of naïve T cells

Phase I: Generation of TCR

Description

  • Initial development occurs in the thymus.

  • Thymocytes begin as double positive (DP) cells with both CD4 and CD8 markers.

Phase II: Thymocyte Selection

Positive Selection

  • Occurs in the thymic cortex via interactions with cortical thymic epithelial cells (cTECs).

  • Aim: Select DP thymocytes that can bind MHC molecules with low to intermediate affinity.

  • Outcome: Approximately 95% of DP thymocytes fail positive selection.

  • Ensures MHC restriction of developing TCRs.

Lineage Commitment

  • Transition from DP thymocytes to single positive (SP) thymocytes (CD4+ or CD8+).

  • Mechanisms of lineage commitment are debated but critical to development.

Negative Selection

  • Occurs in the medulla through interactions with medullary thymic epithelial cells (mTECs) and dendritic cells (DCs).

  • Objective: Eliminate SP thymocytes with self-reactive TCRs.

  • mTECs express AIRE (autoimmune regulatory element) to present tissue-restricted peptides.

Mechanisms of Central Tolerance

  • Clonal Deletion: Apoptosis of auto-reactive thymocytes.

  • Clonal Arrest: Non-maturing auto-reactive thymocytes.

  • Clonal Anergy: Inactivation rather than deletion of auto-reactive thymocytes.

  • Clonal Editing: Re-arrangement of TCR-α genes in auto-reactive thymocytes.

Phase III: Activation of Naïve T Cells

Overview

  • Naïve T cells (Th0 cells) persist in peripheral tissues until antigen encounter.

  • TCR can only recognize processed antigens presented by MHC.

Steps of Activation

  1. TCR Signaling: Engagement with antigen-MHC complexes.

  2. Costimulatory Interaction: Required contact with costimulatory ligands from dendritic cells (DCs).

  3. Cytokine Signaling: Cytokines drive differentiation and proliferation of T cells.

Signal Requirements for T Cell Activation

Two Signal Hypothesis

  • Signal 1: Antigen-specific TCR engagement.

  • Signal 2: Contact with costimulatory ligands (e.g., CD28 on T cells binding CD80/CD86 on APCs).

  • Importance of ICOS for maintaining activation post-initial engagement.

Immunological Synapse

  • Contains both central and peripheral supramolecular activating complexes that enhance TCR-MHC interactions.

Co-stimulatory and Co-inhibitory Receptors

Co-stimulatory Receptors

  • CD28: Primary for initial activation; enhances TCR-induced proliferation.

  • ICOS: Expressed by memory and effector T cells, maintains activation.

Co-inhibitory Receptors

  • CTLA-4: Induces inhibitory mechanisms; higher affinity than CD28.

  • PD-1: Helps regulate T cell tolerance in chronic infections.

Cytokine Signals in T Cell Differentiation

  • IL-2: Key cytokine inducing proliferation during T cell activation.

  • Polarizing cytokines direct the differentiation of T cells into various subsets.

Polarizing Cytokines and T Helper Cell Subsets

Th1, Th2, Th17, Treg, TFH Subsets

  • Th1: IL-12 driven, produce IFN-γ for intracellular pathogens.

  • Th2: IL-4 driven, involved in responses to worms and allergies.

  • Th17: TGF-β + IL-6, regulate immunity to extracellular bacteria and fungi.

  • Treg: Govern immune response suppression and autoimmunity.

  • TFH: Support B cell differentiation and humoral immunity.

Conclusion

  • T cell activation occurs in lymph nodes requires processing and presentation of antigen by DCs.

  • Activation involves critical signals that determine differentiation into specialized subsets, ensuring adequate immune responses against various pathogens.