Cytokines and CD4 T cell effector functions

1. Cytokines and CD4 T cell effector functions • Activated T cells change their migration patterns • Activated CD4 T cells can make different types of cytokines • There are many cytokines involved in immune reactions • Some are made by APCs, others by T cells • Cytokines can work together or in opposition • CD4 Th1 responses are dominated by IFN-g production and a phagocytic cell response. • CD4 Th2 responses are dominated by IL-4 production and the stimulation of an "allergic" type response. • The class of the response may be important to rid particular kinds of infections. Chapter 6

2. CD8 CD4 CD8 CD4 1 1 inappropriate activation leads to cell inactivation inappropriate activation leads to cell inactivation 2 CD4 Th2 CD8 killer CD4 Th1 Diverse outcomes of immune activation of mature abT cells naive Activation, proliferation, differentiation effectors Th1 vs Th2 is defined by distinctive pattern of cytokine expression How are these cell fate decisions made?

3. Effector T cells have altered homing properties Promotes homing to lymph nodes Promotes homing to inflamed tissues

4. Regulation of the class of the T helper response • Innate immune cells are key antigen presenting cells. • Dendritic cells • Macrophages • Cell:cell contact dependent signals are important for naïve T cell activation. • MHC+peptide • B7 molecules • Cytokines produced by antigen presenting cells and other innate immune cells can direct the character of the immune response. • IL-12 • IFN-g • IL-4 • T cell derived contact signals and cytokines can direct many other cell functions. • CD40L • IL-4 • IFN-g

5. The Th1 pathway is the response to microbes that infect or activate macrophages and to those that activate NK cells The Th2 pathway is the response to helminths (worms) and allergens (?) [associated with little macrophage activation] TH0 Class switch to neutralizing and mast-cell binding isotypes (IgE). Activation of eosinophils Macrophage activation and stimulation of C’ fixing Ig isotypes

9. Cytokines have pleiotropic and redundant functions • Pleiotropy • —n. • The control by a single protein of several distinct and seemingly unrelated phenotypic effects. [Greek pleion, more; trop, to turn.] — • Redundant • -Adj • Exceeding what is necessary or natural; superfluous. • 4. Of or involving redundancy in the transmission of messages (e. g. “presidential mistake”)

11. Sensitization to cell death

13. Cytokines can exhibit synergy and antagonism • synergy • n. • The interaction of two or more agents or forces so that their combined effect is greater than the sum of their individual effects. • antagonism • n. • 1. Hostility that results in active resistance, opposition, or contentiousness-like students in a classroom • 3. Biochemistry. Interference in the physiological action of a chemical substance by another having a similar structure.

18. The immune system: a Rube Goldberg device?

23. Effector T cells *cell bound (contact dependent) * * * *

24. Evidence for Th1 and Th2 phenotypes • CD4 T cell clones can be grown in tissue culture by stimulating periodically with antigen-presenting cells+antigen, followed by expansion with IL-2. • Resulting clones tend to fall into two extreme categories as judged by differences in cytokine production. • Th1 cells produce interferon gamma (IFN-g) • Th2 cells produce interleukin-4 (IL-4) • In certain types of infection a Th1 response is protective, while a Th2 response is not or vice versa. • Often Th1 responses protect against intracellular protozoan parasites such as trypanosomes and leishmania. • Th2 responses are important in protection against multicellular helminth or nematode worms.

25. Figure 6-34 Activated Th2 cell CD40L-B cell activation IL-4 IL-5-activation of eosinophils IL-10-supsn of TH1 IL-4 induces T cell growth and production of IgE IL-3 GM-CSF IL-5-induces development of eosinophils Eotaxin- causes eosinophils to accummulate

26. DiseasePrevalence Mycobacteria Tuberculosis35 million Leprosy 1 million Protozoa Malaria 44 million Chagas disease 1 million Leishmaniasis 2 million Sleeping sickness 1.5 million Helminths Ascariasis 1.8 million Schistosomiasis 1.7 million Filariasis 5.7 million Trichuriasis 1 million HIV/AIDS 86 million intracellular extracellular

27. Th1 but not Th2 response is protective for Mycobacterium leprae.

28. BALB/c Anti-IL-4 Leishmania Regulating the class of the Th response may be important Th2 response dies of infection BALB/c Leishmania Th1 response resistance! Th1 response disease resistance B6 Leishmania

29. Figure 6-33

31. The Th2 (but not Th1) reponse provides protection against the large, multicellular parasite Schistosomiasis (a helminth worm). IgE mediated activation of eosinophils

32. Figure 7-26

33. IL-4 is an important cytokine for IgE responses

34. Dendritic Cells Th-0

37. Granuloma formation can isolate infection in cases where the microbe is not completely cleared. Shown is a case of tuberculosis.

38. Concepts in CD4 T cell function • Activated CD4 T cells carry out their functions through soluble cytokines (IL-4, IFN-g) and cell bound signals (FasL and CD40L). • CD4 T cell responses can become polarized to the Th1 or Th2 phenotypes. • Cytokines produced by innate immune cells can regulate the differentiation to Th1 (IL-12, IFN-g) or Th2 (IL-4). • The types of cytokines that CD4 T cells produce can be important in resistance to infectious disease. Next time, NK cells; Parham 8.13-8.15