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- 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

CD8killer

CD8 CD4

CD4Th1

CD4Th2

naive

effectors

Activation, proliferation, differentiation

Diverse outcomes of immune activation of mature T cells

Th1 vs Th2 is defined by distinctive pattern of cytokine expression

1 1

2

inappropriateactivation

leads to cell inactivation

inappropriateactivation

leads to cell inactivation

CD8 CD4

How are these cell fate decisions made?

Promotes homing to lymph nodes Promotes homing

to inflamed tissues

Effector T cells have altered homing properties

• Innate immune cells are key antigen presenting cells.Dendritic cellsMacrophages

• Cell:cell contact dependent signals are important for naïve T cell activation.

MHC+peptideB7 molecules

• Cytokines produced by antigen presenting cells and other innate immune cells can direct the character of the immune response.

IL-12IFN-IL-4

• T cell derived contact signals and cytokines can direct many other cell functions.

CD40LIL-4IFN-

Regulation of the class of the T helper response

Macrophage activation and stimulation of C’ fixing Ig isotypes

Class switch to neutralizing and mast-cell binding

isotypes (IgE). Activation of eosinophils

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

Pleiotropy—n.The control by a single protein of several distinct and

seemingly unrelated phenotypic effects. [Greek pleion, more; trop, to turn.] —

Redundant-Adj1. Exceeding what is necessary or natural;

superfluous.4. Of or involving redundancy in the transmission of

messages (e. g. “presidential mistake”)

Cytokines have pleiotropic and redundant functions

Sensitization to cell death

synergyn.1. The interaction of two or more agents or forces so that

their combined effect is greater than the sum of their individual effects.

antagonismn.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.

Cytokines can exhibit synergy and antagonism

The immune system:

a Rube Goldberg device?

Effector T cells

**

*cell bound(contact dependent)

**

• 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-) • 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.

Evidence for Th1 and Th2 phenotypes

Figure 6-34

Activated Th2 cellCD40L-B cell activationIL-4IL-5-activation of eosinophilsIL-10-supsn of TH1

IL-3

GM-CSF

IL-5-induces

development of

eosinophils

Eotaxin- causes eosinophils to accummulate

IL-4 induces T cell growth and production of IgE

Disease Prevalence

MycobacteriaTuberculosis 35 millionLeprosy 1 million

ProtozoaMalaria 44 millionChagas disease 1 millionLeishmaniasis 2 millionSleeping sickness 1.5 million

HelminthsAscariasis 1.8 millionSchistosomiasis 1.7 millionFilariasis 5.7 millionTrichuriasis 1 million

HIV/AIDS 86 million

intracellular

extracellular

Th1 but not Th2 response is protective for Mycobacterium leprae.

B6

BALB/c

Leishmania

Leishmania

Th2 responsedies of infection

Th1 responsedisease resistance

BALB/c

Leishmania

Th1 responseresistance!

Anti-IL-4

Regulating the class of the Th response may be important

Figure 6-33

The Th2 (but not Th1) reponse provides protection against the large, multicellular parasite Schistosomiasis

(a helminth worm).

IgE mediated activation of eosinophils

Figure 7-26

IL-4 is an important cytokine for IgE responses

Th-0

Dendritic Cells

Granuloma formation can isolate infection in cases where the microbe is not completely cleared.

Shown is a case of tuberculosis.

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-) 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