L 5 T Lymphocytes

T Lymphocytes - Study Notes

Instructor Information

  • Course Code: MICRD 0579

  • Instructor: Michael Volin, Ph.D.

  • Contact: mvolin@Midwestern.edu

Objectives

  • Understand the development of T lymphocytes from stem cells in the bone marrow to mature T helper or cytotoxic lymphocytes.

  • Diagram the T cell antigen receptor (TCR), identifying its key features and structures, and explain its function in the immunological synapse.

  • State activation requirements for naïve T helper cells and memory T helper cells.

  • Compare and contrast subclasses of T helper cells based on induction factors, cytokine production, and related immune responses.

  • Describe activation of cytotoxic T lymphocytes and the mechanisms of cytotoxicity in CTL and other cytotoxic cells.

The Thymus and T Cell Maturation

  • The thymus is essential for T cell education which includes:

    • Acquisition of TCR (antigen specificity)

    • Development of self-tolerance

    • Learning about HLA restriction

  • DiGeorge’s syndrome: A condition linked to thymic dysfunction.

  • Thymic involution occurs post-puberty.

T Cell Ontogeny

  • Characterized by:

    • Anatomical compartments:

    • Bone marrow

    • Thymus (cortex, medulla)

    • Peripheral blood, lymph nodes, spleen

    • Cell surface molecules expressed.

T Cell Development Steps

  1. Bone Marrow Stem Cell

    • Migrate to the Thymus

  2. Thymus:

    • Medulla

    • Cortex

    • Mature T helper cell or Cytotoxic T cell (CTL)

    • Pre-αβT cell entering as double positive CD3+

    • Pre-Tα, TCRβ, CD3+, CD4+, CD8+ TCRα, TCRβ.

Selection Processes in the Thymus

  • Positive Selection:

    • CD4+CD8+ immature thymocytes must bind HLA class I and II with appropriate affinity.

    • Failure to do so leads to apoptosis.

  • Negative Selection:

    • Remaining cells that recognize self HLA presenting self peptide on dendritic cells undergo apoptosis or become anergic.

    • This process teaches self-HLA restriction.

Central T Lymphocyte Tolerance

  • Central Tolerance:

    • Tolerance acquired during ontogeny.

    • Involves immature double positive T cells and leads to apoptosis upon strong antigen recognition.

    • Mainly consists of self antigens presented in the thymus.

Results of Selection Processes

  • Over 90% of thymocytes die due to rigorous positive and negative selection.

  • The surviving T cells exiting thymus are:

    • α/β TCR+, CD3+, CD4+ or CD8+

    • Self-HLA restricted and self-tolerant

    • Capable of responding to foreign antigens in the context of self MHC

  • A smaller population possesses γ/δ TCR and leaves thymus without selection.

Surface Markers on Stem Cells

  • Stem cells migrating to the thymus express the following:

    1. CD3

    2. CD3, CD4, and CD8

    3. CD4 and CD8

    4. Chemokine receptors

    5. Chemokine receptors and CD3

True Statements on Positive Selection

  1. It does not occur in bone marrow.

  2. Maintains self-tolerance.

  3. Maintains HLA restriction.

  4. It occurs in Pre-T cells not expressing α/β TCRs.

Circulation of Mature Naïve T Cells

  • Upon leaving the thymus, mature T cells:

    • Enter blood and lymphatic vessels, then home to secondary lymphoid tissue.

    • Constant recirculation; about 2% of total pool enters a new lymph node every hour (approximately 10^4 lymphocytes per second).

    • Recirculation increases the likelihood of encountering antigens.

    • Specific interactions between lymphocytes and endothelial cells facilitate this process.

Clonal Selection Theory

First Exposure to Antigen

  • Interaction of antigen with epitope “C” generates:

    • Effector cells

    • Memory cells

  • Clonal expansion results in various effector quantities like (10^4, 10^6, 10^8).

Subsequent Exposure to Antigen

  • Repeated encounters lead to further clonal expansion, increasing effector and memory cells.

Activation of T Lymphocytes

  • B cells typically handle extracellular antigens.

  • T cells are activated by recognizing intracellular or cell-associated antigens.

  • CD4+ T helper cells secrete cytokines, while CD8+ cytotoxic T cells target and kill infected or cancerous cells.

Recognition of Antigens by T Cells

  • Most exogenous antigens are processed by dendritic cells and presented to:

    1. CD4+ T helper cells

    2. CD8+ T cytotoxic cells.

T Cell Antigen Receptor (TCR) Complex

  • TCR:

    • Part of the immunoglobulin supergene family.

    • Comprised of α and β chains with conserved (C) and variable (V) domains.

    • Responsible for recognizing antigen and HLA on antigen-presenting cells (APC).

  • CD3:

    • A chaperone for TCR.

    • Critical for signaling.

  • Zeta (ζ) chains (CD247):

    • Integral signaling molecules.

Antigen Processing by APCs

  • Antigen is phagocytized or endocytosed, leading to processing into peptide fragments.

  • Peptide is then presented via HLA class II molecules, engaging receptors on CD4+ T helper lymphocytes.

Activation of CD4+ T Helper Cells

Required Components

  1. Exogenous derived antigen peptide presented on HLA class II.

  2. TCR complex engagement.

  3. CD4 binding to HLA class II.

  4. Co-stimulatory signals including CD28 binding to B7.

  5. IL-2 and other cytokines required for full activation.

Co-Receptors for T Cell Activation

  • CD4:

    • Facilitates HLA class II binding to TCR.

    • Works exclusively with the CD4+ cell subset.

  • CD8:

    • Facilitates HLA class I binding to TCR.

    • Exclusive to CD8+ cell types.

Costimulation Dynamics

  • Positive Co-Stimulatory Interactions:

    • Examples include:

    • B7 (CD80):CD28

    • CD40:CD40L (CD154)

  • Negative Co-Stimulatory Interactions:

    • Examples include:

    • PD-L1:PD-1

    • B7 (CD80):CTLA-4

Peripheral T Lymphocyte Tolerance

  • Types of Tolerance:

    • Anergy: Functional inactivation due to lack of secondary signals (e.g., without B7-CD28).

    • Activation-Induced Cell Death: Apoptosis occurs in activated T cells under persistent stimulation.

    • Regulatory T Cells (Tregs):

    • Characteristics: CD4+, CD25+, FoxP3+.

    • Suppress activation of other T cells by producing inhibitory cytokines.

Factors Influencing T Helper Cell Polarization

  • Antigen presentation type, molecular structure, exposure route, and host HLA type determine the immune response (i.e., whether a Th1 or Th2 profile develops).

Activation of CD8+ Cytotoxic T Lymphocytes

  • CD8+ T cells are primarily cytotoxic; they recognize endogenous antigens associated with HLA class I, especially those from tumors or intracellular pathogens.

Cytotoxicity Mechanisms of CD8+ T lymphocytes

  • CD8+ T cells utilize two pathways to induce apoptosis in target cells:

    • Perforin/Granzyme Pathway:

    • Perforins create pores in target cell membranes, allowing granzymes to enter and induce apoptosis.

    • Fas Pathway:

    • Interaction between FasL on cytotoxic cells and Fas on target cells, triggering apoptosis through caspases.

Characteristics of Cytotoxic Cells

  • Killing Mechanism:

    • Involves cytoplasmic granules loaded with perforins and granzymes, leading to apoptosis.

    • TNF-α/β and IFN-γ also contribute to cell-mediated cytotoxicity.

Unique Features of Natural Killer (NK) Cells

  • NK Cells:

    • Large granular lymphocytes originating from common lymphoid stem cells in the bone marrow.

    • Markers include CD56+ and CD16+.

    • Do not have memory and are part of the innate immune response.

Recognition Mechanism by NK Cells

  • NK cells utilize Killer Inhibitory Receptors (KIR) that bind HLA class I, allowing them to differentiate between healthy and unhealthy cells based on HLA expression.

Macrophage Cytotoxicity

  • Upon activation, macrophages can exert cytotoxic effects through mechanisms like TNF-α release and production of reactive oxygen and nitrogen species.

Questions

  • For clarifications or further inquiries, please contact the instructor.