Cell-Mediated Immunity Notes

Lymphocyte Development and Selection

Lymphoid lineage cells are identified by their surface molecules.

  • Mature, naïve B lymphocytes express two isotypes of antibody or immunoglobulin: IgM and IgD on their surface membrane.
  • Mature, naive T cells express a single genetically related molecule called the T-cell receptor (TCR) on their surface.

Selection of T and B Lymphocytes

  • Lymphoid progenitors develop in the bone marrow (primary lymphoid organ).
  • B lymphocytes complete their development in the bone marrow, identified by the immunoglobulin chains they produce.
  • Immature lymphocytes destined to become T cells leave the bone marrow and mature in the thymus, the second primary lymphoid organ.

T Lymphocyte Development

  • Pre-thymic cells are double negative T lymphocytes because they do not express CD4 or CD8 on their surface.
  • These cells rearrange the beta and alpha chains of the TCR while co-expressing the CD3 complex, as well as the CD4 and CD8 co-receptors, making them double positive.

T Cell Selection Process

A selection process removes cells that:

  • Bind to normal self-antigens, preventing autoimmunity.

  • Lack attraction for the surfaces of antigen-presenting cells (APCs).
    This process involves exposing developing T cells to major histocompatibility complex (MHC) antigens.

  • TCRs capable of binding with low affinity receive a positive selection signal to divide and mature.

  • Failure to recognize self-MHC results in a failure of positive selection.

  • Strong binding to self MHC molecules and self-peptide induces apoptosis (negative selection) to prevent autoimmune disease.

CD4 and CD8 Expression

  • Double positive cells co-express CD4 and CD8, but:

    • Express only CD8 if their TCR binds class I molecules.
    • Express only CD4 if their TCR binds class II molecules.

  • At this point, they are referred to as single positive.

    • CD4+ cells recognizing class II MHC become “helper” T cells (Th).
    • CD8+ cells recognizing class I MHC become cytotoxic T lymphocytes (CTLs).

Mature T Lymphocytes Expression

  • Mature T lymphocytes express:
    • Antigen receptors (TCRs) consisting of α and β polypeptide chains (sometimes γ and δ).
    • CD3 (on all T cells).
    • CD4 or CD8 molecules (on subpopulations of T cells).
    • Other important molecules (e.g., CD28, CD40L).

Differentiation of T Cells

T cells are classified functionally into:

  • T helper cells
  • T cytotoxic cells
  • T regulatory cells

T Helper Cell Activation and Clone Selection

When a naïve Th cell meets its specific antigen, it:

  • Proliferates
  • Differentiates into effector cells (secreting cytokines) and memory cells (resting cell).

T Helper Subsets

Based on the profile of cytokines produced, T helper cells are subdivided into 3 subsets:

  • Th1: Enhance cell-mediated immune responses (e.g., IL-2).
  • Th2: Enhance humoral immune responses (e.g., IL-4).
  • Th17: Enhance inflammation (e.g., IL-17).

Th1 and Th2 Regulations

Th1 and Th2 can produce positive feedback for their own type of cells and inhibit the effects of the other type.

T-Cell Activation

  1. Dendritic cell (specialized APC) samples antigen, processes antigen, and migrates to the draining lymph node.
  2. T-cell activation (signal 1): antigen is presented on MHC II and recognized by TCR on Th (CD4+) cell. Endogenous or cross-presented antigen is presented on MHC I to Tc (CD8+) cell.
  3. Proliferation and survival (signal 2): costimulatory signal via interaction of B7 protein (CD80/86) on dendritic cell and CD28 on naïve T cell.
  4. Th cell activates and produces cytokines. Tc cell activates and can recognize and kill virus-infected cells.

CTLA-4

CTLA-4 is an immunoregulatory molecule expressed on activated Th and Tregs, downregulating the immune response by competitive binding to B7-1 and B7-2 on APCs.

  • Agonists: Rheumatoid arthritis
  • Antagonists: Melanoma

Major Functions of T Cells

T cells:

  • Mediate cell-mediated immunity.
  • CD4+ T cells help B cells make antibodies and produce cytokines to recruit phagocytes and activate other leukocytes.
  • CD8+ T cells directly kill virus-infected cells.
  • Mediate delayed cell-mediated hypersensitivity (type IV).
  • Involved in acute and chronic cellular organ rejection.

CELL-MEDIATED IMMUNITY

Cell-mediated immunity battles:

  • Facultative intracellular pathogens (live inside phagocytic cells).

  • Obligate intracellular pathogens (cannot replicate outside of host cells).

  • Mediated primarily via macrophages and CD8+ T cells through the Th1 response.

  • T cells direct all aspects of the immune system via the secretion of cytokines.

  • NK cells also have a role.

MACROPHAGES/B CELLS

The Th1 response activates macrophages and B cells via IFN-γ.

  • IFN-γ activates macrophages to eradicate intracellular pathogens.
  • Induces B cells to class switch to produce opsonizing IgG antibodies that assist macrophages with phagocytosis.

Macrophage-Th Cell Interaction

  • The binding of the TCR of the naïve T cell to the MHC class II–peptide complex of the macrophage provides the first signal to the T cell to begin its activation, providing the antigenic specificity of the response.
  • Co-stimulatory molecules on the macrophage provide the second signal, and cytokines secreted by the macrophage and the activating T cells themselves induce the proliferation (clonal expansion) and differentiation of the T cells into effector cells and memory cells.
  • Effector cells leave the secondary lymphoid tissue, enter into circulation, and travel to the site of the infection.

T Cell Activation and Differentiation

  • The responding T cell secretes its own growth-promoting cytokines and also expresses receptor molecules for these factors.
  • IL-2 is the most important growth factor for T cells, stimulating the proliferation of clones of T cells specific to that antigen.
  • T cells provide IFN-γ, which promotes macrophage activation that also helps to activate T cells.
  • The production of IL-12 by the macrophage also helps to activate the T cells.
  • Together, IL-12 and IFN-γ also help to promote the differentiation of the naïve T cell into a Th1 cell.
  • The reaction mediated by the Th1 cell via macrophage and CD8+ T cell activation is often referred to as the delayed-type hypersensitivity (DTH) reaction.

CYTOTOXIC T LYMPHOCYTES (CTLS)

CTLs recognize the cell they will kill by interaction between their TCR and the MHC class I peptide complex on the surface of the target cell.

  • Normal cells producing normal “self” peptides should not be targeted by CD8+ T cells.
  • Cells infected with an intracellular pathogen or expressing neoantigens reflective of tumor transformation can be targeted by CD8+ T cells.
  • Transplanted tissues between nonidentical individuals are often targeted by CTLs as abnormal.

Th1 Cell and Interferons

  • The Th1 cell secretes IL-2, which acts on CD8+ cells to enhance their differentiation and cloning via cross priming.
  • Interferons produced in the area will increase the expression of MHC molecules to make target cells more susceptible to killing.

Cross Presentation (Cross Priming)

Dendritic cells (DCs) can present antigens to CD8+ T cells via cross presentation, in addition to presenting antigens on MHC class II molecules to CD4+ T cells.

  • Dendritic cells (DCs) are able to ingest a virally infected cell and present viral antigens within a MHC class I molecule to CD8+ T cells.
  • Therefore, DCs may activate or prime both CD4+ T cells and CD8+ T cells specific for the same pathogen.
  • The activation of naïve CD8+ T cells into activated CTLs and memory cells occurs via the activation of CD4+ T cells and the production of cytokines such as IL-2.

CTL Killing Mechanism

CTLs kill their target cells by delivering toxic granule contents that induce apoptosis.

This process occurs in 4 phases:

  • Attachment to the target cell (mediated by TCR, CD8, and others).
  • Activation (concentrate granules against attached target cell).
  • Exocytosis of granule contents (perforin and granzymes).
  • Detachment from the target cell.

Mechanisms of Cytotoxic T-Cell Killing

The death of the target cell is mediated by:

  • Perforin creating pores in the membrane of the target cell, allowing granzymes to enter and induce the activation of “death domain."
  • Cytokines such as IFN-γ with TNF-α or TNF-β inducing apoptosis.
  • Activated CTLs expressing Fas ligand (FasL), which binds to Fas on the target cell, resulting in death.

NK CELLS

NK cell-killing is another cell-mediated effector mechanism enhanced by the action of Th1 cells.

  • Effector Mechanisms: Perforin, granzymes, cytokines (identical to CTL).
  • The only difference is how they recognize the antigen (no need for class I MHC).

ADCC (Antibody-Dependent Cell-Mediated Cytotoxicity)

ADCC bridges humoral and cell-mediated effector systems.

  • A number of cells with cytotoxic potential (NK cells, macrophages, neutrophils, and eosinophils) have membrane receptors for the Fc region of IgG.

  • When IgG is specifically bound to a target cell, the cytotoxic cells can bind to the free Fc “tail” and subsequently cause lysis of the target cell.

    • Lytic enzymes
    • Tumor necrosis factor
    • Perforin/granzymes