The Effect of Antigen Stimulation on the Migration of Mature T Cells from the Peripheral Lymphoid Tissues to the Thymus
Developmental Immunology
The Effect of Antigen Stimulation on the Migration of Mature T Cells from the Peripheral Lymphoid Tissues to the Thymus , CHARLES L. HARDY DALE I. GODFREY and ROLAND SCOLLAY
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0 From the Centenary Institute of Cancer Medicine and Cell Biology , Locked Bag no 6, Newtown, NSW , Australia , 2042
Although the maturation and export of T cells from the thymus has been extensively studied, the movement of cells in the opposite direction has been less well documented. In particular, the question of whether T cells which have been activated by antigen in the periphery are more likely to return to the thymus had been raised but not clearly answered. We examined this issue by activating T cells present in the periphery with their cognate antigen, and assessing migration to the thymus. TCR-transgenic cells from OT-I mice(Thyl.2/), which recognlse the ovalbumin peptide OVA257_264 in the context of H-2Kb, were transferred into otherwise unmanipulated Thyl.1 / C57BL/6 mice. Recipient mice were injected i.v. with 5 ktg peptide (SIINFEKL) approximately 24 hours later. The numbers of donor-derived (Thyl.2+) cells in the thymus and peripheral lymphoid tissue were determined. The results clearly show increased numbers of transgenic cells in the thymus 3 days after antigenic stimulation. However, since numbers of transgenic cells increased in the spleen and LN in about the same proportion, the data do not support the notion that there is highly increased selective migration of activated T cells to the thymus. Rather, they suggest that a sample of peripheral cells enters the thymus each day, and that the mature immigrants detected in the thymus merely reflect the contents of the peripheral T cell pool. Abbreviations: CFSE, carboxy fluorescein (diacetate) succinimidyl ester; LN, lymph node; MLN, mesenteric lymph node; OT-I mice, OVA257_264-specific TCR-transgenic mice; OVA257_264, ovalbumin peptide
Thymus; T lymphocytes; Homing; Recirculation; Transgenic
INTRODUCTION
The thymus is the primary source of T cells for the
peripheral lymphoid organs. T cells produced in the
thymus migrate to the spleen and lymph nodes (LN),
especially early in life, and in the absence of a thymus
these organs remain essentially devoid ofT cells. This
pathway has been extensively quantitated in a number
of species, and in young adult animals represents an
export rate of about 1% of thymocytes per day
(Scollay et al., 1980; Scollay and Shortman, 1985)
.
The reverse pathway, of mature T cells migrating
from the periphery back into the thymus is less often
considered, although several studies have shown that
this is not a major pathway in normal animals
(Dumont et al., 1984; Michie et al., 1988; Hirokawa
et al., 1989; Agus et al., 1991)
. Our own unpublished
data suggest that about 1% of the mature phenotype
cells in the thymus may be mature T cell immigrants
(Coward and Scollay, in preparation). Some studies
have suggested that this pathway might preferentially
be used by activated T cells. An early report indicated
that activated antigen-specific T cells migrated to the
thymus, and persisted there, whereas migration of
non-activated cells to the thymus was not detected
(Naparstek et al., 1982). Similarly,
Fink et al. (1984)
demonstrated that peripheral T cells activated in vivo
provide a greater contribution to the thymic memory
CTL response than non-activated cells. In that study,
it was not possible to determine the proportion of
thymocytes which were donor derived. More recently, it
was shown that blasts (generated in parent F
combinations) homed to the thymus, and represented
approximately 0.4% of mature T thymocytes,
although the rate of homing was greatly increased by
irradiation of hosts
(Agus et al., 1991)
. Others have
shown that, compared to ?naive? CD4+ T cells, there is
a preferential accumulation of antigen-experienced T
cells in the rat thymus
(Bell et al., 1995; Westerman et
al., 1996)
. As is the case for ?normal? peripheral T
cells
(Hirokawa et al., 1989)
, accumulation of
activated cells within the thymus is largely restricted to
the medulla
(Pabst and Binns, 1989; Agus et al.,
1991; Westermann et al., 1996)
.
One shortcoming of the above studies is that
thymic immigration of in vivo-activated clonal T cell
populations has not been analysed. As part of a longer
study on migration of mature cells into the thymus,
we have addressed this question in a model where
TCR transgenic T cells present only in the periphery
could be stimulated with their cognate peptide, and
their migration to the thymus assessed. OT-I mice
(Hogquist et al., 1994)
carry a transgene for a MHC
class I-restricted TCR with Vc2 and V135 variable
regions. The TCR recognises the ovalbumin peptide
OVA257_264 presented by H-2Kb, the MHC haplotype
of C57BL/6 mice. In these mice, the great majority of
peripheral T cells are CD8/CD4-, (...truncated)