Cytokine Regulation of Effector Functions 
in Immune Responses 
Tim R. Mosmann, Ph.D. — International Research Scholar 
Dr. Mosmann is Professor and Chair of the Department of Immunology at the University of Alberta, 
Edmonton. He received his Ph.D. degree in microbiology at the University of British Columbia, Vancouver, 
and obtained postdoctoral training in Toronto and Glasgow as a fellow of the Medical Research Council. 
After four years as Assistant Professor in Immunology at Alberta, he spent eight years as a senior scientist 
at DNAX Research Institute in Palo Alto. He then returned to the University of Alberta. 
AFTER infection the host's immune system 
must respond by specifically recognizing 
the invading organism and inducing the effector 
mechanisms that will most effectively destroy the 
pathogen. Determination of the correct antigen- 
specific recognition structures is mediated by the 
process of clonal selection, whereby B or T cells 
are selectively activated if they already express 
receptors specific for the infecting agent. Choice 
of the appropriate effector mechanism is deter- 
mined to a large degree by T cells and the cyto- 
kines they secrete. 
The immune system can attack infectious 
agents by a number of means. Antibody is highly 
effective at neutralizing toxins and free virus and 
at coating bacteria to enhance their recognition 
and destruction by phagocytic cells. There are 
also various cell-mediated cytotoxic mecha- 
nisms, such as killer T cells, macrophages, and 
granulocytes, that are most useful against intra- 
cellular infectious agents. Cytokines secreted by 
activated T cells regulate the accumulation and 
activation of these cells at sites of infection, and 
some cytokines also have direct cytotoxic 
functions. 
Recruitment and activation of macrophages 
and granulocytes occur strongly during a delayed- 
type hypersensitivity (DTH) reaction, which pre- 
sents an effective response against intracellular 
infections. In contrast, antibody responses are 
normally more effective against extracellular 
pathogens. It has long been known that antibody 
and DTH responses are often "either-or" re- 
sponses of the immune system, although the 
mechanism of this reciprocal regulation has only 
been partially resolved. 
Several years ago we and others described two 
types of T cell that secrete very different patterns 
of cytokines. THl cells produce interIeukin-2 
(IL-2), interferon-7 (IFN-7), and lymphotoxin 
(LT), whereas only TH2 cells produce IL-4, IL-5, 
IL-6, IL-10, and P6OO. These cytokines have mul- 
tiple and profound effects on various aspects of 
the immune response, and so THl and TH2 cells 
have markedly different functions. 
TH2 cells induce antibody production by B 
cells. In particular, a strong TH2 response is asso- 
ciated with high production of IgE, the antibody 
that causes allergy. Although THl cells can also 
induce antibody production under some circum- 
stances, these cells are much more effective at 
inducing DTH. Thus the choice of THl or TH2 
responses influences the balance between DTH 
and antibody responses. 
Although the THl and TH2 patterns account 
for a major part of the immune response during 
certain infections, these probably represent ex- 
tremes, and there are other T cells with different 
cytokine secretion phenotypes. These other pat- 
terns may be involved in the many possible types 
of immune response that occur against different 
infectious agents. 
Since the type of immune response induced 
against a particular pathogen is often characteris- 
tic for that agent, the choice of effector function 
must be precisely regulated. It appears that cross- 
regulation by TH 1 and TH2 cytokines plays a ma- 
jor role in determining the effector functions. 
Some of this cross-regulation is now understood: 
IFN-7 produced by THl cells can inhibit prolifer- 
ation of TH2 cells, and IL-10 produced by TH2 
cells inhibits the activation of THl cells. 
Effector T cells such as TH 1 and TH2 are proba- 
bly derived from precursor cells that secrete only 
IL-2. After initial stimulation with antigen, these 
cells presumably differentiate into THl, TH2, 
and other cells. This process is influenced by cy- 
tokines — e.g., IL-4 encourages the production of 
more cells that secrete IL-4. However, the full 
regulation of this process is largely unknown, and 
this is currently an active area of investigation in 
our laboratory and others. Since the differentia- 
tion process is quite rapid (e.g., a few days), we 
are developing single-cell cytokine detection 
methods so that we can follow differentiation of 
single clones of cells. 
Two methods are currently possible: the mRNA 
for different cytokines can be measured in single 
cells after amplification by polymerase chain re- 
action, and cytokine protein secreted by single 
cells can be analyzed by a colorimetric spot assay 
using anticytokine monoclonal antibodies. Both 
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