Functional Heterogeneity in CD4-hearing 
T Lymphocytes 
H. Kim Bottomly, Ph.D. — Associate Investigator 
Dr. Bottomly is also Associate Professor in the Section of Immunobiology and the Department of Biology 
at Yale University School of Medicine. She received her Ph.D. degree from the University of Washington, 
Department of Biological Structure, where she studied with Roy Schwartz. Her postdoctoral training was 
received in the field of immunology with Don Mosier at the NIH. 
LYMPHOCYTE interactions during an immune 
response are necessary for the induction of 
antigen-specific lymphocytes. The resulting ef- 
fector phase of an immune response is described 
as either humoral or cell mediated: each of these 
phases combats different types of microorgan- 
isms. Although these effector mechanisms are 
well characterized, the precise mechanism by 
which the response to a given antigen or in- 
fectious agent is directed into the humoral or 
cell-mediated mode is not known. What is clear, 
however, is that both types of immunity depend 
on the activation of CD4-bearing T lymphocytes, 
which in turn induce other cell types to respond 
to the foreign antigen. These responses include 
activation of B cells to proliferate and to secrete 
antibody, induction of delayed-type hypersensi- 
tivity reactions, activation of CDS cytolytic T 
cells, and activation of macrophages. 
Two questions were then asked. 1) Could the 
same CD4 T cell activate all these target cells, 
therefore mediating both humoral and cell- 
mediated responses? 2) Is the CD4 T cell popula- 
tion functionally heterogeneous; i.e., do some 
CD4-bearing T cells activate B cells and play a 
primary role in the induction of humoral immu- 
nity, and do some activate macrophages and CD8- 
bearing T cells and play a primary role in cell-me- 
diated immunity? 
For several years we have focused on the hetero- 
geneity in CD4 T cell function and the activation 
conditions that lead to it. These studies have suc- 
cessfully shown that monoclonal CD4 T lympho- 
cytes, obtained by T cell cloning and expansion 
in tissue culture, belong to two distinct subsets of 
T cells. One subset can help B cell antibody se- 
cretion but cannot activate macrophages; the 
other set activates macrophages but is a poor B 
cell activator. To reflect their main functions, 
these two subsets are called helper T cells (Th2) 
and inflammatory T cells (Thl). The distinct 
functional abilities of Th2 and Thl subsets is re- 
flected in their release, upon activation, of dis- 
tinct panels of cytokines. Several cytokines are 
produced selectively by one or the other subset. 
In particular, interleukin-2, interferon-7, and 
lymphotoxin are produced by the Thl but not 
Th2 cell subset. Interleukin-4 is produced by the 
Th2 but not Thl cell subset. 
Thus there is a correlation between cytokine 
production and function. Interleukin-4 is a po- 
tent B cell activator involved in B cell prolifera- 
tion and secretion of immunoglobulins IgGl and 
IgE. By contrast, interferon-7, lymphotoxin, and 
interleukin-2 are associated with responses in- 
volving the activation of macrophages, lysis of 
target cells, and induction of cytolytic T cells, 
which is consistent with the known function of 
these cytokines. One can conclude from these 
studies that T cells are committed to the release 
of a distinct panel of lymphokines when acti- 
vated, with the released effector molecules de- 
termining their effector function. 
Recent studies in this laboratory have focused 
on determining whether functionally distinct 
subsets of CD4 T cells exist in vivo and whether 
the selective activation of one subset or the other 
has the expected functional consequences. Nu- 
merous clinical studies have suggested that 
various immunization schemes induce primarily 
a humoral or cell-mediated immune response. It 
is critically important to determine if such major 
differences in protective immunity reflect differ- 
ences in the proportion of CD4 T cell subsets 
activated. If this is true, one might propose that 
the form of the antigen or the antigen presenta- 
tion must somehow direct which CD4 T cell will 
be preferentially activated. To test this possibil- 
ity, several questions about normal CD4 T cells 
have been asked. 
First, is there a separation of resting CD4 T cells 
into subsets? To answer this, an analysis of the 
responses to antigens that give rise to primarily 
humoral or cell-mediated immunity has been 
performed. When humoral immunity dominates, 
Th2-like CD4 T cells are activated. By contrast, 
when cell-mediated immunity dominates, Thl- 
like CD4 T cells are activated. Thus, during the 
course of an immune response, CD4 T cells may 
become specialized in their functional capabili- 
ties, and these T cells in vivo resemble, in their 
activities, Thl and Th2 cloned lines. 
Second, when during development or activa- 
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