L18: Specialized Functions of T cell Subsets

what is the role of CD28 in T cell activation?

CD28 on naïve T cells binds CD80 (B7.1) or CD86 (B7.2) on APC.

What does CTLA-4 do to inhibit T cell activity?

CTLA-4 on activated T cells is upregulated and binds to CD80/CD86 on the APC.

What kind of mechanisms are used to turn T cell activity up or down?

conserved mechanisms (i.e. binding CD80/CD86)

what does T cell signaling induce to itself?

-number of changes in T cell phenotype (how it looks) and function (what it does)

-T cell proliferation: clonal expansion

-Decreased and increased integrin expression (so it can leave LN and cross endothelium to get to tissue)

-Increased chemokine receptor expression (so it can find the site of infection)

-Expression of specific effector molecules

What is the biggest change induced during T cell signaling?

IL-2 secretion and expression of high affinity IL-2 receptor (IL-2R or CD25)

what effector molecules are impacted by T cell signaling?

•Cytokines (IFN-γ, TNF-α, IL-4, IL-17, IL-10)

•Cytotoxic proteins (granzyme, perforin)

•Killer receptors (CD56, CD94, NKG2D)

what is the 3rd signal of the 3-signal hypothesis?

-cytokine production

-triggers signaling pathway that then activates specific transcription factors

what does each transcription factor lead to in T cell differentiation?

gene expression that differentiates the activated T cell into the specific functional phenotype needed to control the given infection that originally initiated the process (i.e., at the time of Ag processing and presentation).

what do the cytokine-induced signals from the APC to the naive T cell establish?

T cell differentiation pathways

what is the primary role of CD4 helper T cells?

cytokine production

what is the primary role of CD8 cytotoxic T lymphocytes?

killing of infected or altered cells

What is the primary role of regulatory T cells (Treg)?

suppression of T cell immunity

what is the primary role of NK T cells?

killing of cells expressing particular lipid Ag

what is the primary role of gamma delta cells?

surveillance and response (i.e. cytokine and killing) at mucosal sites

what are the subsets of CD4 T cells determined?

-cytokine environment

-Activation of different transcription factors and production of different cytokines.

what are the three general purposes of CD4 T cell effectors?

1.Promote cell-mediated immune responses (adaptive AND innate)

2.Promote humoral immune responses

3.Regulate (suppress) immune responses

What are CD4 T helper 1 (Th1) cells induced by?

APC production of IL-12 and production of IFN-γ (NK, CD8, CD4 Th1)

what is the signature cytokine of CD4 T helper 1 (Th1) cells?

IFN-γ

What is IFN-γ?

-Potent activator of CD8 CTL, NK cells, macrophages.

-Upregulates MHC Class II and costimulatory molecules - a positive feedback loop for T cell responses

-Stimulates production of Ab isotypes that efficiently bind/activate complement. This leads to increased opsonization and phagocytosis of microbes through binding of C'-Ab complexes by Fc and C' receptors.

What is the specialty of CD4 T helper 1 (Th1) cells?

cell mediated immunity (CD8,NK)

what is the effect of Th1 cytokines?

cytokines increase efficiency of macrophage killing mechanisms (reactive oxygen species, nitric oxide, proteolytic enzymes) and CTL function.

What is CD4 T helper 2 (Th2) cells induced by?

IL-4 production

What are the signature cytokines of CD4 T helper 2 (Th2) cells?

IL-4, IL-5, IL-13

what is the speciality of CD4 T helper 2 (Th2) cells?

humoral immunity (Ab, B cells), allergy, asthma, parasites

what is the role of IL-4?

stimulates Ab production and isotype class switching to IgE.

what is the role of IL-5?

growth and activation factor for eosinophils

what is the role of IL-13?

-promotes mucus production which can help prevent infection at mucosal surfaces (increased barrier protection).

-Increased mucus helps expel parasites, but also is deleterious in asthma.

What are the alternatively activated macrophages activated by IL-4 and IL-13 cooperation efficient in?

tissue repair, not good APCs

How do IgE's used to activate a cell?

-IgE binds Fcε receptors on mast cells and eosinophils.

-Receptors are crosslinked when allergen or parasite binds to IgE variable domains, activating the cell.

What are CD4 T helper (Th17) cells induced by?

APC production of IL-6, IL-23, TGF-β.

what are the signature cytokines of CD4 T helper (Th17) cells?

IL-17, IL-22

what are the roles of IL-17?

-Induces production of IL-8 and other cytokines which promote recruitment and function of PMN

-Stimulates release of antimicrobial peptides from epithelial cells

What is the specialty of CD4 T helper (Th17) cells?

neutrophilic responses against bacterial and fungal infection

What are T regulatory (Treg) cells?

Specialized subset of T cells that express high levels of CD25 (IL-2 receptor) and the transcription factor FoxP3 (signature molecule!)

what is the specialty of T regulatory (Treg) cells?

-Regulation (suppression) of T cell responses

-to shut-down activated T cells (turn off responses to infection) and to prevent autoimmune responses (surveillance).

what is a key factor in the suppressive action of T regulatory (Treg) cells?

production of IL-10 and TGF-β

what are T regulatory (Treg) cells induced by?

TGF-β

What are characteristics of natural Tregs (nTreg) cells?

-differentiated in thymus (by TCR affinity)

-5 to 10% of CD4+8- thymocytes (most Tregs are CD4+)

-FoxP3+CD25high

What are characteristics of adaptive or inducible Tregs?

-Thymus-independent

-Differentiated in periphery from Th0 cell

FoxP3+CD25high

Secrete IL-10 and TGF-β

what is the function of subsets of Treg cells?

suppress CD4, CD8, DCs, etc.

What are the mechanisms of suppression of Tregs?

-contact dependent

-contact independent

what are the types of contact-dependent mechanisms of T reg suppression?

•Anergy: CTLA4, PD1L

•Killing: CD95 (Fas)

what is the suppressive activity of Treg cells initiated by?

initiated in Ag-dependent manner (TCR binding), but maintained in absence of Ag

What is the cross-regulation of Th1-Th2 axis?

•IFN-γ inhibits IL-4-mediated Th2 differentiation

•IL-4 and IL-13 inhibit Th1 differentiation and CD8 CTL function

•IFN-γ from CD4 Th1 cells inhibit IL-4 and Th17 differentiation

What is the primary role for CD4 T cells in cytolysis?

-production of cytokines which increases the activation and killing efficiency of other cells.

-However, it has lately been demonstrated that CD4 T cells can exert direct cytolytic function on virus-infected and tumor cells.

How are CD8 cytotoxic T lymphocytes (CTL) cells activated?

-Can receive help from CD4 Th1 through IFN-γ production

-CD4 help not needed when there is a robust innate response with lots of IFN-γ from NK cells

-CD8 cytotoxic activity can be inhibited by IL-4 and IL-13 from CD4 Th2 cells

what can cytokine production by the CD8 T cell (especially IFN-gamma) activate?

activate neighboring CD8 T cells, NK cells, and macrophages, increasing the cell-mediated immune response (positive feedback loop).

how do CD8 cytotoxic T cells recognize Ags?

recognize in the context of MHC Class I on altered self cells (infected, tumor, damaged) and kills target cell by multiple mechanisms (next slide).

What are the pathways CD8 CTL cells use to kill target cels?

-Perforin/granzyme: release of pre-formed granules

-Fas/Fas ligand (FasL):direct receptor-ligand binding

-TNF-α: death signals through TNF-α receptor

What are NK T cells?

-A specialized subset of T cells that express both T (CD3, usually CD4) AND NK cell proteins (CD56, NKG2D)

-Very rapidly exit thymus and found in higher concentrations at sites of potential pathogen entry

-Activated very rapidly

what kind of Ag do NK T cells see?

See lipid antigens presented in the context of the MHC Class I-like molecule CD1

what is the role of NK T cells?

-Key to protection against mycobacterial and fungal pathogens that contain mycolic lipids in their cell walls

-Induce death of target cell (cytolysis) through NK killing receptors (e.g., NKG2D)

what is the difference between NK cells and NKT cells?

NK cells are innate while NKT cells are adaptive.

Where are γδ T Cells found in high concentration?

epithelium (skin, gut mucosa)

what is the role of γδ T Cells?

-Bind phospho-Ag from pathogens and stressed cells in MHC-independent manner

-Now are realizing that there are different functional phenotypes, with a defining cytokine, which parallels conventional T cell differentiation

-Encounter Ag at barriers, are rapidly activated and differentiate, then can migrate to LN to help in activation and differentiation of B cells and conventional T cells

What is the default phenotype of γδ T Cells?

Default is an IFN-γ-producing type 1 phenotype

What happens when everything goes RIGHT with the T cells?

At the right time and right place and to the right level, adaptive immune responses eliminate invading pathogen and repair damage.

What happens if T cells are in the wrong place, for extended time, or at exaggrerated levels?

-T cell response becomes pathogenic

−CTL: bystander tissue damage, cytokine storm

−Th1: delayed type hypersensitivity reaction, autoimmunity (e.g., diabetes, MS)

−Th2: asthma, allergy

Th17: autoimmunity (RA, SLE, IBD)

what is the primary response

-cells are activated, proliferate, then contract as the infection is cleared.

-Memory cells are established in the contraction phase

what is the secondary/memory response?

-On re exposure to the same pathogen, those memory cells are READY TO GO.

-They respond (i.e., expand) more quickly and, generally, to a greater magnitude.

how is each memory T cell subset different?

-Each subset is phenotypically and functionally distinct

-Location

-Trafficking potential

-Response to Ag

what is immunologic memory established with?

-exposure (induction)

-Age (maintenance)

What is immunosenescence?

age-related decline in immunity

what is cyclosporine?

inhibits calcineurin

what are anti-CD3 and anti-CD52 drugs?

block MHC-TCR signaling or deplete T cells en masse

what are IL-2 receptor antibodies or antagonists drugs?

prevent IL-2 signal transduction, so no T cell growth

What are CTLA-4-Ig drugs?

blocks CD80/86 on APC, so no costimulation during Ag presentation

what are TNF-α inhibitors?

various treatments (e.g., Humira, Adalimumab, Etanercept) that interfere with TNF-α