 |
|
|
| Research
Group |
|
| Research
Interests |
|
Research
in the Developmental Immunology Group is focussed on the development and
selection of T lymphocytes. During their maturation in the thymus immature
precursor T cells must rearrange and express T cell receptor (TCR) a,
b, g and d
genes. In addition they must undergo two distinct cell fate specification
events, first choosing between the ab and gd
T cell lineages and subsequently (for the ab
lineage) between CD4 and CD8 T cell fates. In parallel to the CD4/CD8
lineage choice immature ab T cells undergo
negative and positive selection, a process which eliminates precursors
with high TCR affinity for self antigens and retains cells with moderate
TCR affinity that will be able to respond subsequently to foreign antigens.
The Developmental Immunology Group investigates many aspects of this complex
developmental program, with special emphasis on lineage commitment and
TCR repertoire selection.
| Current Projects |
|
ab/gd
lineage commitment. T cells of the ab and
gd lineages develop from a common intrathymic
precursor, but little is known about the lineage commitment process. It
is clear, however, that ab/gd
lineage choice does not depend solely upon the expression of ab
or gd TCR, since some precursor cells can be
rescued to the ab lineage via expression of
a functional gd TCR. We are currently investigating
such lineage "mismatched" cells in detail in order to better
understand the molecular basis for ab/gd
lineage commitment. We are also studying the developmental pathway of
a subset of fetal thymic gd cells that express
highly restricted TCR g and TCR d
chains and migrate selectively to the epidermis.
NKT cell development. NKT cells are an unusual subset of mature
T cells that express a CD1d-specific semi-invariant ab
TCR as well as markers usually associated with NK cells such as NK1.1
and members of the Ly-49 receptor family. We are interested in the developmental
pathway of NKT cells in the thymus, with particular emphasis on the role
played by Ly-49 receptors in NKT cell maturation. To this end we are producing
and analyzing transgenic mouse strains that express the semi-invariant
TCR, as well as inhibitory and activating members of the Ly-49 receptor
family.
TCR
repertoire selection. The mechanisms that distinguish positive and
negative selection of developing ab lineage
thymocytes remain obscure, particularly since both processes are initiated
by recognition of self peptide: MHC complexes (expressed by non-lymphoid
thymic components) by TCR expressed on immature thymocytes. We are currently
attempting to dissect positive and negative selection by generating transgenic
mice that express selecting MHC ligands exclusively on thymic cortical
epithelial cells (implicated in positive selection) and not on thymic
medullary hematopoietic cells (implicated in negative selection). By crossing
such mice with other transgenic mice expressing TCR specific for self
MHC: peptide ligands we will assess the ability of thymic cortical epithelial
cells to induce positive and negative selection, as well as the quantitative
impact of negative selection on the TCR repertoire.
| Selected
publications |
|
Ferrero,
I., Wilson, A., Beermann, F., Held, W. and MacDonald, H.R. 2001. T cell
receptor specificity is critical for the development of epidermal gd
T cells. J. Exp. Med. 194:1473-1483.
Radtke,
F., Ferrero, I., Wilson, A., Lees, R., Aguet, M. and MacDonald, H.R. 2000.
Notch1 deficiency dissociates the intrathymic development of dendritic
cells and T cells. J. Exp. Med. 191:1085-1093.
Eberl,
G. and MacDonald, H.R. 1998. Rapid death and regeneration of NKT cells
in anti-CD3e- or IL-12-treated mice: A major
role for bone marrow in NKT cell homeostasis. Immunity 9:345-353.
MacDonald,
H.R., Lees, R.K. and Held, W. 1998. Developmentally regulated extinction
of Ly-49 receptor expression permits maturation and selection of NK1.1+
T cells. J. Exp. Med. 187:2109-2114.
van
Meerwijk, J.P.M., Marguerat, S., Lees, R.K., Germain, R.N., Fowlkes, B.J.
and MacDonald, H.R. 1997. Quantitative impact of thymic clonal deletion
on the T-cell repertoire. J. Exp. Med. 185:377-383.
Ohteki,
T. and MacDonald, H.R. 1996. Stringent Vb requirement
for the development of NK1.1+ T cell receptor-a/b+
cells in mouse liver. J. Exp. Med. 183:1277-1282.
Wilson,
A., de Villartay, J.-P. and MacDonald, H.R. 1996. T cell receptor d
gene rearrangement and T early a (TEA) expression
in immature ab lineage thymocytes : implications
for ab/gd lineage
commitment. Immunity 4:37-45.
|
|
