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Table of Contents
T Cell Activation—Schwartz
T Cell Subsets-Schwartz
T Cell Differentiation— Fowlkes
T Cell Memory and Tolerance—Matzinger
Office of the Chief
Laboratory of Cellular and Molecular Immunology
October 1, 1991 through September 30, 1992
The Laboratory of Cellular and Molecular Immunology was created in November,
1986. Its major task is to perform research on thymus-derived (T) lymphocytes. Its objective
is to understand how these critical cells of the immune system differentiate and function. The
approach is to define problems in whole animal systems, set up in vitro analogs in tissue
culture, and determine the molecular basis for the phenomena. The laboratory employs
techniques from the disciplines of cellular immunology, molecular biology, and protein
During its sixth year, the laboratory has pursued four major areas of research: 1) the
molecular nature of costimulation, 2) the meaning of a half maximal response for interleukin
2 production, 3) T cell receptor aP lineage commitment and the affinity model for repertoire
selection in thymic development and 4) fetal thymic stem cells, T cell life span, T cell
recirculation and tolerance to tissue specific antigens.
T Cell Activation
Studies of T cell activation of normal murine T cell clones of the T^l type have
shown that two signals are required to stimulate the cells to make interleukin-2 (lL-2) and
divide. One signal is given through the antigen-specific receptor that is uniquely expressed
on each clone. The other signal is called costimulation and is delivered through a different
receptor. Our major objective during the past year was to characterize the costimulatory
signal. Other laboratories had identified the B7/BB1 molecule as the inducible ligand on the
APC and CD28 and CTLA-4 on the T cell as potential receptors for costimulation in the
production of interleukin-2 (IL-2). We explored the role of these molecules in a new assay
for costimulation, the induction of competence to respond to interleukin-4 (IL-4). Murine T^l
clones do not respond directly to IL-4. They first must be activated by stimulating them with
antigens and APC. After 24 hr. the activated T cells then proliferate in response to IL-4. We
demonstrated that costimulation is required during the induction phase in order to make the
clones competent to proliferate in response to IL-4. Although supplying costimulation also
led to the production of IL-2, stimulation with this lymphokine was not the only signal
required to gain competence, because addition of IL-2 to a T cell receptor occupancy signal
only allowed the cells to become partially competent to respond to IL-4. We concluded from
these experiments that the costimulatory signal contributes directly to the attainment of full
competence to respond to IL-4. To explore the molecules involved in this costimulation, we
used a recombinant fusion protein between CTLA4 and a human Ig immunoglobulin constant
region. This molecule reacts with B7/BB 1 expressed on activated Buy Intagra antigen-presenting cells.
We showed that CTLA4Ig could inhibit proliferation and IL-2 production of both ThI and
ThO murine clones but not IL-4 production by the latter. In addition it inhibited the ability of
ThI clones to gain competence to respond to IL-4. We concluded from these experiments
that B7/BB1 is the critical ligand involved in costimulation for both IL-2 production and the
gaining of competence to respond to IL-4.
(S. Umlauf, K. Brorson, S. Kitagawa, L. Chiodetti, and R. H. Schwartz, LCMI, MAID; P.
Linsley, Bristol-Meyers Squibb)
T Cell Subsets
When a population of T cells divides in response to an antigenic stimulus a range of
concentrations of the antigen is required to go from no cells dividing to all the cells dividing.
At the concentration required to achieve one-half of the maximal response, it has been
demonstrated that one-half of the cells are dividing. The production of lymphokines by T
cells shows a Intagra 100 similar dose-response curve to antigen. However, the interpretation of the half-
maximal response is not necessarily the same. Either all the cells are producing only one-half
of their maximal potential, or one half of the cells are producing at their full potential while
the other half are producing nothing. To decide between these two alternatives we examined
the production of interleukin 2 by single T cell clones at different concentrations of antigen.
The response appeared to be quantal (all or none) but two different levels of response were
observed, one approximately 3-4 times the other. Furthermore, the dose response curve was
biphasic with a decrease in the number of cells in each group at higher (>30nM) antigen
concentrations. Our interpretation of these results is that induction of transcription of the IL-2
gene is what is quantal. Thus, the group of cells giving the low level of IL-2 production had
only one chromosome being transcribed, whereas the group giving the higher level of IL-2
production was transcribing both chromosomes. The fact that all the cells were not found in
the high positive group at large antigen concentrations possibly reflects a negative feedback
regulation on IL-2 transaiption. Experiments are currently in progress to test these two
(B. Beverly, A. Bendelac, D. Cassell, and R. H. Schwartz, LCMI, NIAE); D. Ailing, NCI,
T Cell Differentiation
During T cell development, thymocytes that are able to recognize self MHC are
signalled to mature (positive selection), whereas those capable of self reactivity are selected to
die (negative selection). Our studies deal with the paradox of how signaling resulting from a
specific TCR-MHC interaction can determine the positive or negative selection events.
Several investigations involving TCR transgneic mice revealed that distinct thymic antigen
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