T Cell Notes

T Cell Phenotypes

Activation of T Cells (Overview)

The Major Histocompatibility Complex (MHC) binds peptide fragments from pathogens and displays them to T cells. MHC molecules are expressed on antigen-presenting cells (APCs), mainly dendritic cells.

  • MHC Class I: Presents peptides to CD8+ cytotoxic T cells.

  • MHC Class II: Presents peptides to CD4+ T helper cells.

The T cell receptor (TCR) recognizes these MHC:peptide complexes.

Structure of the T Cell Receptor

The TCR is a heterodimer of alpha ($\alpha$) and beta ($\beta$) polypeptide chains. Each chain has a variable region domain and a constant region, as well as a transmembrane (TM) region and cytoplasmic tail. The specificity of the TCR is determined by the $\alpha$v and $\beta$v domains, which form the site that contacts the MHC:peptide complex.

The TCR tail does not directly link to intracellular signaling pathways. Instead, the TCR relies on the CD3 complex for signal transduction.

The TCR associates non-covalently with the CD3 complex in the T cell plasma membrane. CD3 is a complex of 5 different polypeptide chains: gamma ($\gamma$), delta ($\delta$), epsilon ($\epsilon$), and zeta ($\zeta$), that associate to form 3 different dimers: $\delta\epsilon$ heterodimer, $\epsilon\gamma$ heterodimer, and $\zeta\zeta$ homodimer.

The protein tyrosine kinases Fyn and Zap-70 associate closely with the cytoplasmic tail of $\epsilon$ and $\zeta$ chains of CD3. These tails contain ITAMs (immunoreceptor tyrosine-based activation motifs).

CD4 and CD8 are co-receptors that bind to MHC molecules. Lck (leukocyte-specific protein tyrosine kinase) associates with the cytoplasmic tails of CD4 and CD8, and intracellular signals emanate from CD4 and CD8.

T-Cell Activation Requirements

T-cell activation requires both antigen presentation and co-stimulatory signals. Without both, a naive T cell will not respond and may become unresponsive.

Naïve T cell activation: TCR/co-receptor (CD28) on the T cell binds to MHC:peptide and B7 on the dendritic cell (DC). This results in high-affinity IL-2R expression, IL-2 secretion, and subsequent T cell division and proliferation, leading to effector cell generation.

T Cell Expansion and Contraction

Following activation, T cells undergo clonal expansion, increasing the number of T cells specific for the antigen. After the infection is cleared, most of these effector cells die off in a contraction phase, leaving behind a pool of memory T cells.

CD4+ T Cell Phenotypes

Naïve T cells can differentiate into different effector phenotypes (Th1, Th2, Treg, Th17) depending on the signals received from the dendritic cell (DC) during T cell priming. A naïve T cell becomes an activated cell, then a Th0 cell, before differentiating further.

  • Th1 cells: Produce IFN$\gamma$, IL-2, and TNF$\alpha$. Involved in inflammatory responses and help for macrophages.

  • Th2 cells: Produce IL-4 and IL-5. Help B cells.

  • Treg cells: Anti-inflammatory, suppress immune responses.

  • Th17 cells: Produce TGF$\beta$.

Signals from APCs

APCs deliver three kinds of signals to naïve T cells:

  1. MHC:peptide complex binding to the TCR (Activation).

  2. Co-stimulatory molecules (e.g., B7.1/B7.2) binding to CD28 (Survival).

  3. Cytokines (e.g., IL-6, IL-12, TGF-$\beta$) (Differentiation).

The amount of pMHC, accessory co-stimulatory molecules, and different cytokine combinations secreted determine T cell fate.

  • High levels of peptide-loaded MHC and co-stimulatory molecules stimulate Th1 responses.

  • Low levels of peptide-loaded MHC and co-stimulatory molecules stimulate Th2 and Treg responses.

Accessory co-stimulatory molecules include CD80/CD86, CD40, OX40L, PD-L1/PD-L2, ICOSL, and CD137, which bind to CD28/CTLA4, CD40L, OX40, PD-1, ICOS, and CD137 on T cells, respectively.

Cytokine Signals

Specific cytokines drive the differentiation of T cells into different subsets:

  • TGF-$\beta$ induces FoxP3 expression, leading to Treg cell development.

  • IL-6 induces ROR$\gamma$t expression, leading to Th17 cell development.

  • IL-12 and IFN$\gamma$ induce T-bet expression, leading to Th1 cell development.

  • IL-4 induces GATA-3 expression, leading to Th2 cell development.

  • TGF$\beta$ and IL-10 induce TŔ1/T3 cells.

IL-10 is a regulatory cytokine secreted by macrophages and dendritic cells, balancing the secretion of IL-12. High IL-12 secretion promotes Th1 responses, while high IL-10 secretion promotes Treg responses.

The balance of TGF-$\beta$ and IL-6 determines Treg vs Th17 development. TGF-$\beta$ switches on FoxP3, while IL-6 switches on ROR$\gamma$t.

T Cell Phenotype Summary

CD4 T cells (MHC Class II)

CD8 T cells (MHC Class I)

TH1, TH2, Treg, Th17

CTL (Cytotoxic T Lymphocytes)

Function

Activate macrophages, B cells, CD8 T cells

Kill virus-infected cells

Target

Intracellular bacteria, toxins

Virus-infected cells, tumor cells

CD4+ T Helper Cell Function

  • Macrophages: Amplify macrophage function.

  • B Cells: Cellular basis of the antibody response.

  • CD8 T Cells: Help for CD8 T cells.

Help for Macrophages

Macrophages clear extracellular bacteria via phagocytosis. Some bacteria (e.g., Mycobacteria) and parasites (e.g., Leishmania) can avoid degradation within macrophages.

Th1 cells activate macrophages via IFN$\gamma$, enhancing:

  • Fusion of lysosomes with phagosomes.

  • Production of toxic oxygen radicals, nitric oxide, and antibacterial peptides.

  • Secretion of cytokines and chemokines to recruit other immune cells.

Activated macrophages express peptide-loaded MHC and co-stimulation, which stimulates TH1 cells to release chemokines, cytokines, and cytotoxins.

  • IFN$\gamma$ induces expression of vascular adhesion molecules and activates macrophages.

  • TNF$\alpha$ and TNF$\beta$ cause local tissue destruction and increase adhesion molecule expression.

  • IL-3/GM-CSF stimulate monocyte production.

Binding of primed Th1 cells to MHC:peptide on macrophages activates Th1 effector functions (IFN$\gamma$ release and membrane-bound TNF$\alpha$ expression). Activated macrophages secrete soluble TNF$\alpha$, further increasing antimicrobial activities.

Macrophage activation is tightly controlled due to the potential for excessive tissue damage. Activation is antigen-specific, initiated by Th cells recognizing MHC:peptide complexes on the macrophage surface.

Help for B Cells

Antigen recognition induces expression of effector molecules by the T cell, which activates the B cell.

TH2 cells interact with B cells via CD40L (CD154) binding to CD40, and release cytokines like IL-4, IL-6, and IL-5, promoting B-cell proliferation and differentiation into memory cells and antibody-secreting plasma cells.

B cells must process and present antigen captured by the B cell receptor to obtain T cell help, acting as antigen-presenting cells.

  • Signal 1: B cell receptor (BCR) signaling.

  • Signal 2: CD40 stimulation.

At the point of contact, T cells and B cells adhere via ICAM-1 and LFA. Cytokines such as IL-4 are released, and the cytoskeleton is polarized (relocation of cytoskeletal protein TALIN) with relocation of the Golgi towards B cell.

T cell subtypes differentiate B cells to produce different antibody isotypes. Proliferation cytokines: IL-2, IL-4, IL-5. Differentiation cytokines: IL-2, IL-4, IL-5, IFN$\gamma$, TGF-$\beta$.

  • IFN$\gamma$ induces IgG2a or IgG3 production.

  • TGF-$\beta$ induces IgA or IgG2b production.

  • IL-2, IL-4, IL-5 induce IgE or IgG1 production.

Th1 cells and Th2 cells are the main T cell subsets for