The Birth of Functionally Distinct T Cell

Subsets
Leonard Chess

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The Birth of Functionally Distinct T Cell Subsets
Leonard Chess1
By the late 1960s and early 1970s, it was already
clear that immune responses were effected by lym-
phoid cells and that an interesting subdivision of
labor existed among populations of lymphocytes
resident in distinct lymphoid organs. Thus, it was known that
thymic-derived T cells migrated from the thymus to populate
lymphoid organs and effected cell-mediated immune responses,
whereas Ab production was mediated by bone marrow-derived
B cells. Moreover, B cell Ab production was found to be depen-
dent on help from thymic-derived T cells. Furthermore, in ad-
dition to this helper function of T cells, it was clear that T cells
mediated other immune functions, including delayed-type hy-
persensitivity (DTH),2 cytotoxic activity and regulatory sup-
pressor functions. A question of paramount importance that
surfaced was whether these various functions of T cells were
conducted by a single T cell with various functions or, on the
contrary, by distinct functional subsets. The seminal experi-
ments of Cantor and Boyse, highlighted in this month’s “Pillars
of Immunology,” provided unequivocal evidence that two ma-
jor subsets of peripheral T cells exist and that they mediate dis-
tinct sets of functions (1). Using the genetically well-defined
allo-antisera to the Ly-1 and Ly-2,3 differentiation Ags, they
were able to isolate two mutually exclusive populations of T
cells expressing either the Ly-1 or the Ly-2,3 surface molecules.
The Ly-1⫹ T cells contained the functional subset responsible
for B cell help and for inducing DTH reactions. In contrast, the
Ly-2,3⫹ subset was devoid of helper cells but contained the cy-
totoxic cells important in mediating cell-mediated cytotoxicity
directed to alloreactive cells (1, 2). Interestingly, the Ly-1⫹ sub-
set did not mediate killing but amplified the killing mediated by
the Ly-2,3 subset. Moreover, the suppressor functions were
found to be largely contained in the Ly-2 subset (3). These find-
ings were rapidly extended to the analysis of human T cells, ini-
tially with heteroantibodies and then with mAbs that defined
the human T cell surface molecules, CD4 and CD8 (4, 5).
These Abs defined functionally distinct human CD4⫹ and
CD8⫹ T cell subsets, which functionally were analogous to the
murine Ly-1 and Ly-2,3 subsets. Later, mAbs were also raised to
the murine CD4 and CD8 molecules (6, 7). The murine CD4⫹
peripheral T cells were exclusively contained within the Ly-1⫹
population and mediated the helper function while the murine
Ly-2 mAbs identified the population of cytotoxic and suppres-
sor populations identical to the Ly-2,3 alloantibodies (6, 8).
Thus, the major T cell subsets in both man and mice were vir-
tually identical in that they comprised analogous functional
1
Address correspondence and reprint requests to Dr. Leonard Chess, Columbia Uni-
versity, College of Physicians and Surgeons, 630 West 168th Street, New York, NY
10032. E-mail address: LC19@columbia.edu
2
Abbreviation used in this paper: DTH, delayed-type hypersensitivity.
Copyright © 2006 by The American Association of Immunologists, Inc.
populations. As will be discussed below, when the CD4 and
CD8 molecules were cloned and sequenced in both species, the
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structural and expression patterns of the molecules were also
highly homologous (9).
A fundamental question that arose from these studies was
whether the two T cell subsets represented two separate lines of
differentiation or whether they were sequential stages of a single
differentiative pathway. In the latter case, one would give rise to
the other. In elegant experiments in which Ly-1 or Ly-2,3 cells
were parked in B mice deprived of all T cells, even after pro-
longed residence of Ly-l cells in B hosts that have been deprived
of Ly-2,3⫹ cells (B-Ly-1 mice), there was no appreciable gen-
eration of Ly-2,3 cells from Ly-l cells, and the Ly-1 cells main-
tained their helper function and did not mediate alloreactive
killing. Conversely there was no appreciable conversion to
Ly-1⫹ cells in B-Ly-2,3 mice (10). Moreover, long-term in vitro
culture of CD4⫹ or CD8⫹ T cell clones in vitro confirmed the
phenotypic stability of both the function and the CD4 or CD8
surface expression. Together these studies demonstrated that
the two subsets belong to distinct differentiation lineages and
are not sequential stages of a single progression. Moreover, it is
now recognized that the CD4⫹ and CD8⫹ subsets in fact arise
from a common precursor, the double-positive CD4⫹CD8⫹
thymocytes. It is this double-positive population in the thymus
that gives rise to either the CD4 or CD8 lineage.
In addition to these functional distinctions, CD4⫹ and
CD8⫹ T cell subsets also differed in a cognitive sense. Thus,
CD4⫹ T cells were found to be MHC class II restricted,
whereas CD8⫹ T cells were found to be MHC class I restricted
(11, 12). Moreover, the expression of the CD4 and CD8 cell
surface molecules correlates as well with the class of MHC mol-
ecules that restricts Ag recognition as with function. These cor-
relations strongly suggested that the CD4 and CD8 molecules
play a very important role in T cell responses by actually inter-
acting with distinct conserved portions of the MHC class I and
MHC class II molecules. In fact, when the CD4 and CD8 mol-
ecules were cloned in both man and mouse, the molecular se-
quences in both CD4 and CD8 molecules responsible for di-
rectly binding to MHC class II or MHC class I were defined
(13, 14). The fact that the genetic programs that define the T
cell subsets are intimately linked to the two predominant MHC
pathways has biological significance not only in the thymus
where the two subsets are selected on the basis of MHC but also
in the periphery where the subsets mediate their distinctive
functions. Thus, CD4⫹ T cells mediate B cell help and DTH
responses by interacting with and inducing the MHC class II-
expressing B cells, dendritic cells, and macrophages, whereas the
CD8⫹ subsets can in principle interact with and kill all nucle-
ated cells, which can express MHC class I molecules and thus
0022-1767/06/$02.00
3860
can present peptides derived from the universe of intracellular
pathogens and tumors. Thus, the CD4 and CD8 molecules are
not just markers of T cell subsets but in fact are functionally
important molecules at the core of T cell recognition where they
function in concert with the Ag-specific ␣,␤ TCR to recognize
MHC/Ag-peptide complexes.
Finally, perhaps the most significant clinical ramification of
the identification of T cell subsets to date was that it led to the
identification of the CD4 molecule which turned out to also
function as the cellular receptor for HIV (15, 16). In fact, Abs to
CD4 (which were being made as the AIDS epidemic was in its
infancy) permitted the initial clinical identification of AIDS as
a disease. Moreover, the loss of the CD4⫹ subset of T cells dur-
ing clinical evolution of HIV infection provided insight into the
pathophysiology of this devastating immunodeficiency disease
and will perhaps ultimately lead to the treatment of the disease
(17, 18).
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different Ly antigens. II. Cooperation between subclasses of Ly⫹ cells in the genera-
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PILLARS OF IMMUNOLOGY
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