T Helper Cell Cytokine Profiles

A presentation on the Cytokine profiles displayed by Helper T Cells during an Immune Response

1. T - helper cells’ cytokine profiles Dariyus z kabraji Immunology MSc 1 biotechnology roll no 18 Batch 1

2. T cells T cells are those specialized cells of the immune system which mature in the thymus. Mature T cells are stored in secondary lymphoid organs (lymph nodes, spleen, tonsils, appendix, and Peyer’s patches in the small intestine). These cells circulate in the bloodstream and the lymphatic system. After they first encounter an infected or abnormal cell, they are activated and search for those particular cells . Killer (cytotoxic) T cells attach to antigens on infected or abnormal (for example, cancerous) cells. Killer T cells then kill these cells by making holes in their cell membrane and injecting enzymes into the cells. Suppressor (regulatory) T cells produce substances that help end the immune response or sometimes prevent certain harmful responses from occurring . For this presentation, let us concern ourselves with the third type- Helper T Cells DARIYUS Z KABRAJI

3. Helper T cells Helper T cells help other immune cells. Some helper T cells help B cells produce antibodies against foreign antigens. Others help activate killer T cells to kill infected or abnormal cells or help activate macrophages, enabling them to ingest infected or abnormal cells more efficiently . They help the activity of other immune cells by releasing T cell cytokines. Some helper T cells help B cells produce antibodies against foreign antigens. Others help activate killer T cells to kill infected or abnormal cells or help activate macrophages, enabling them to ingest infected or abnormal cells more efficiently. Their importance in the immune system can be seen by observing HIV infections, which target the mature T helper cells (which express the CD4 protein and are termed CD4 T cells ) DARIYUS Z KABRAJI

4. Cytokines Cytokines are a large class of proteins playing vital roles in cell signalling. They are released by cells to manipulate the behaviour of others, and in some cases, manipulate the releasing cell itself. Cytokines include chemokines , interferons , interleukins, lymphokines , tumour necrosis factors but not hormones or growth factors. They act through receptors, and are especially important in the immune system; cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. DARIYUS Z KABRAJI

5. Path followed during an immune response Recognition Verification Proliferation Maturation DARIYUS Z KABRAJI

6. Recognition (Signal 1) (APCs) endocytose foreign material (typically bacteria or viruses), which undergoes processing, then travel from the infection site to the lymph nodes. Once at the lymph nodes, the APC begin to present antigen peptides that are bound to Class II MHC, allowing CD4+ T cells that express the specific T cell Receptors against the peptide/MHC complex to activate. When a TH cell encounters and recognises the antigen on an APC, the TCR-CD3 complex binds strongly to the peptide-MHC complex present on the surface of professional APCs. CD4, a co-receptor of the TCR complex, also binds to a different section of the MHC molecule. These interactions bring these proteins closer together , allowing the intracellular kinases present on the TCR, CD3 and CD4 proteins to activate each other via phosphorylation. DARIYUS Z KABRAJI

7. Verification (Signal 2) This verification step is a protective measure to ensure that a T cell is responding to a foreign antigen. If this second signal is not present during initial antigen exposure, the T cell presumes that it is auto-reactive. This results in the cell becoming anergic ( anergy is generated from the unprotected biochemical changes of Signal 1). Anergic cells will not respond to any antigen in the future, even if both signals are present later on. These cells are generally believed to circulate throughout the body with no value until they undergo apoptosis . The second signal involves an interaction between CD28 on the CD4+ T cell and the proteins CD80 (B7.1) or CD86 (B7.2) on the professional APCs. Both CD80 and CD86 activate the CD28 receptor. These proteins are also known as co-stimulatory molecules. The second signal is considered obsolete since signal 1 does the activation. DARIYUS Z KABRAJI

8. Proliferation Once the two-signal activation is complete the T helper cell (TH) then allows itself to proliferate. It achieves this by releasing a potent T cell growth factor called interleukin 2 (IL-2) which acts upon itself in an autocrine fashion. DARIYUS Z KABRAJI

9. Maturation After many cell generations, the TH cell's progenitors differentiate into effector TH cells, memory TH cells, and regulatory TH cells. A Effector TH cells secrete cytokines, proteins or peptides that stimulate or interact with other leukocytes, including TH cells. B Memory TH cells retain the antigen affinity of the originally activated T cell, and are used to act as later effector cells during a second immune response (e.g. if there is re-infection of the host at a later stage). C Regulatory T cells do not promote immune function, but act to decrease it instead. Despite their low numbers during an infection, these cells are believed to play an important role in the self-limitation of the immune system; they have been shown to prevent the development of various auto-immune diseases . DARIYUS Z KABRAJI

10. Subtypes Proliferating helper T cells that develop into effector T cells differentiate into two major subtypes of cells known as TH1 and TH2 cells These subtypes are defined on the basis of the specific cytokines they produce i.e. TH1 and TH2 produce various types of interleukins to provoke various bespoke responses Exception: interleukin-12 (IL-12) plays an essential role during TH1 development, however IL-12 is not produced by helper T cells themselves, but by certain professional APCs, such as activated macrophages and dendritic cells. Future Prospects include studying proliferation, stabilization and epigenetic remodelling of th1 and th2 cytokines DARIYUS Z KABRAJI

11. Subtypes DARIYUS Z KABRAJI

12. Cytokine Profile Helper T cells are found in two distinct cell types, Th1 and Th2, distinguished by the cytokines they produce and respond to and the immune responses they are involved in. Th1 cells produce pro-inflammatory cytokines like IFN-gamma, TNF-b and IL-2, while Th2 cells produce the cytokines IL-4, IL-5, IL-6 and IL-13. The cytokines produced by Th1 cells stimulate the phagocytosis and destruction of microbial pathogens while Th2 cytokines like IL-4 generally stimulate the production of antibodies directed toward large extracellular parasites (see “IL-4 signalling Pathway”). IL-5 stimulates eosinophil responses, also part of the immune response toward large extracellular parasites (see “IL-5 signalling Pathway”) Th1 and Th2 are produced by differentiation from a non-antigen exposed precursor cell type, THP. Exposure of THP cells to antigen by antigen-presenting cells may result in their differentiation to Th0 cells, not yet committed to become either Th1 or Th2 cells, although the existence of Th0 cells is controversial. Cells committed as either Th1 and Th2 cells are called polarized, whether they are effector cells actively secreting cytokines or are memory cells. The stimulation of THP cells by exposure to antigen-presenting cells induces the proliferation of undifferentiated cells, and their expression of IL-2 and IL-2 receptor. The differentiation of Th1 cells and Th2 cells depends on the cytokines they are exposed to. IL-12 causes Th1 differentiation and blocks Th2 cell production (see “IL12 and Stat4 Dependent signalling Pathway in Th1 Development” pathway), while IL-4 causes Th2 differentiation and antagonizes Th1 development. IL-18 also induces Th1 differentiation (See “IL-18 signalling pathway”). Polarized Th1 and Th2 cells also express distinct sets of chemokine receptors that further modify their homing and other cellular responses (see “Selective expression of chemokine receptors during T-cell polarization” pathway). Improved understanding of Th1 and Th2 differentiation will improve our overall understanding of the immune system, its response to infection and aberrant responses that lead to disease. DARIYUS Z KABRAJI

13. Cytokine Profile DARIYUS Z KABRAJI

14. Models of Helper T cells TH 1 Model TH1 cells produce interferon-gamma (IFN-gamma) and tumour necrosis factor-beta (TNF-beta, also known as lymphotoxin ). Cytokines in the TH1 response maximise the killing efficiency of the macrophages and the proliferation of cytotoxic CD8+ T cells. TH 2 Model TH2 cells produce interleukin-4 (IL-4), interleukin-5 (IL-5) and interleukin-13 (IL-13), among numerous other cytokines. Cytokines of the TH2 system stimulate B-cells into proliferation, to undergo antibody class switching, and to increase antibody production. DARIYUS Z KABRAJI

15. Models of Helper T cells TH 1 Model The Type 1 cytokine IFN-gamma increases production of interleukin-12 by dendritic cells and macrophages, and by positive feedback of IL-12 stimulating IFN-gamma production, promotes the TH1 cytokine profile . IFN-gamma also inhibits the production of interleukin-4 , an important cytokine associated the Type 2 response, and thus it acts to preserve its own response. TH 2 Model The Type 2 pathway increases the production of IL-4 on helper T cells and also expresses IL-10 which inhibits IL-2 and IFN-gamma It promotes both the production of its own cytokines while inhibiting the establishment of the TH1 response, ensuring that once the T cell has made that choice, it stays that way DARIYUS Z KABRAJI

16. TH 1 Model Produces a cytokine profile that causes inflammation and activates certain T cells and macrophages . Delayed hypersensitivity TC cell activation Production of opsonization -promoting IgG Abs (i.e., Abs that bind to the high affinity FcRs of phagocytes and interact with complement, such as IgG2a in mice) TH 2 Model Activates mainly B cells and immune responses that depend upon Ab. Stimulates eosinophil activation and differentiation Provides help to B cells Promotes the production of relatively large amounts of IgM , IgE , and non complement-activating IgG isotypes Supports allergic reactions Models of Helper T cells DARIYUS Z KABRAJI

17. References Daniel Mucida , Hilde Cheroutre ; The Many Facelifts of CD4 Helper Cells; Advances in Immunology, Volume 107, Chapter 5 Albert’s Molecular Biology Of The Cell; Chapter 25: The Adaptive Immune System: Effector Helper T Cells Help Activate Other Cells of the Innate and Adaptive Immune Systems DARIYUS Z KABRAJI