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D A Witherden

Publications and source records attributed to D A Witherden.

7 recordsLinked to original sources
PubMed2000

CD81 and CD28 costimulate T cells through distinct pathways.

We have examined the role of CD81 in the activation of murine splenic alphabeta T cells. Expression of the CD81 molecule on T cells increases following activation, raising the possibility of a role for this molecule in progression of the activation process. Using an in vitro costimulation assay, we show that CD81 can function as a costimulatory molecule on both CD4+ and CD8+ T cells. This costimulation functions independently of CD28, and unlike costimulation through CD28, is susceptible to inhibition by cyclosporin A. Strikingly, the pattern of cytokine production elicited by costimulation via CD81 is unique. IL-2 production was not up-regulated, whereas both IFN-gamma and TNF-alpha expression significantly increased. Together our results demonstrate an alternate pathway for costimulation of T cell activation mediated by CD81.

Animals↗
PubMed1995

Antigen-independent maturation of CD2, CD11a/CD18, CD44, and CD58 expression on thymic emigrants in fetal and postnatal sheep.

We have compared the expression of CD2, CD11a/CD18, CD44, and CD58 and alpha beta and gamma delta T cells emigrating from the fetal and postnatal thymus. We report that both gamma delta and the CD4+CD8- and CD4-CD8+ subsets of alpha beta T cells express mature levels of the adhesion molecules CD11a/CD18, CD44, and CD58 upon emigration from the thymus. Whereas CD44 is up-regulated on gamma delta + thymocytes prior to export, down-regulation of both CD11a/CD18 and CD58 occurs prior to emigration from the thymus, suggesting that down-regulation of these molecules may be a final maturational step taken by developing gamma delta T cells before their export from the thymus. In contrast, there is continued up-regulation of CD2 on gamma delta and alpha beta T cells upon emigration from the thymus and as they move into the mature peripheral T-cell pool. There was also a marked reduction in the number of CD2+ gamma delta T cells exported during fetal development that was associated with a marked reduction in the percentage of CD2+ gamma delta thymocytes exported. The postthymic maturation of CD2 and the other changes in adhesion-molecule expression appear to be independent of extrinsic antigen, as the same changes were observed in the antigen-free environment of the fetus as in the postnatal lamb, which has been exposed to extrinsic antigen. It thus appears that these changes in adhesion-molecule expression are as a result of the normal maturation pathway from a developing thymocyte to a mature peripheral T cell.

Animals↗
PubMed1994

CD45RA expression of gamma delta and alpha beta T cells emigrating from the fetal and postnatal thymus.

We have compared the expression of CD45RA on alpha beta and gamma delta T cells emigrating from the fetal and postnatal thymus. The fetal and postnatal thymus export both CD45RA+ and CD45RA- T cells. The number of gamma delta +CD45RA+ T cells was remarkably constant regardless of stage of ontogeny or T cell maturity. Around 5-8% of gamma delta thymic emigrants, thymocytes and peripheral blood lymphocytes expressed CD45RA in both fetal and postnatal animals. In contrast to gamma delta T cells, up to one quarter of both fetal and postnatal alpha beta emigrants expressed CD45RA. Post-thymic maturation of CD45RA expression of alpha beta emigrants, which occurred both before and after birth, appeared to be antigen independent.

Animals↗
PubMed1994

Changes in thymic export of L-selectin+ gamma delta and alpha beta T cells during fetal and postnatal development.

We have used the technique of in situ intrathymic injection of fluorescein isothiocyanate to examine L-selectin expression on gamma delta and alpha beta T cells immediately after emigrating from the thymus of fetal and postnatal animals. We found that the percentage of L-selectin+ thymocytes exported per day decreased by half after birth and that the export of T cells from the thymus does not rely on expression of the peripheral lymph node homing receptor, L-selectin. Analysis of L-selectin on emigrant and mature T cell subsets revealed a remarkable heterogeneity of expression, both in terms of the numbers of cells expressing this molecule as well as the level of expression. gamma delta T cells, reportedly not having a propensity for homing to lymph nodes, not only contained the highest proportion of L-selectin+ cells, but also expressed far more of this molecule than either CD4+CD8- or CD4-CD8+ alpha beta T cells. Furthermore, those emigrant T cells expressing L-selectin are somewhat immature in their expression of this molecule. Subsequent maturation resulted in up-regulation of L-selectin on mature peripheral blood T cells, maturation that was clearly independent of extrinsic antigen. This antigen-independent post-thymic maturation appeared to occur as part of the normal progression from immature thymocyte to mature peripheral T cell in both fetal and postnatal animals.

Aging↗
PubMed1994

Changes in thymic export of gamma delta and alpha beta T cells during fetal and postnatal development.

The thymus plays an essential role in the generation and selection of T cells and exports approximately 0.5-1% of thymocytes per day in young animals and considerably fewer in older animals. To date there have been no studies directly examining fetal thymic export in any species. Using the technique of intrathymic injection of fluorescein isothiocyanate, followed by an assay for green fluorescent cells in the periphery and for the expression of cell surface antigens on these cells, we have compared directly the export of T cells from the fetal and postnatal ovine thymus. While the thymus exports both alpha beta and gamma delta T cells, our results demonstrate that the proportion of thymic gamma delta T cells that are exported per day is much higher than that of thymic alpha beta T cells. Moreover, the export rate of gamma delta T cells increased from approximately 1 in every 60 gamma delta thymocytes per day emigrating from the fetal thymus to 1 in every 20 from the postnatal thymus. In addition, we identify a population of CD5+CD4-CD8-gamma delta-. T cells emigrating from the fetal thymus but greatly reduced among thymic emigrants after birth. These findings have several implications regarding the mechanisms and control of selection of both gamma delta and alpha beta T cells.

Animals↗
PubMed1990

Non-random migration of CD4+, CD8+ and gamma delta+T19+ lymphocytes through peripheral lymph nodes.

The experiments described in this paper have examined the migration of three fluorochrome-labelled T-lymphocyte subsets (CD4+, CD8+ and gamma delta+T19+) on a single passage from blood to lymph, through prescapular lymph nodes. Lymphocytes obtained from prescapular efferent lymph were labelled in vitro with fluorochrome and returned to the blood of the same animal. Over the next 2 days, lymph was continuously monitored and the cells in all collections, including the one used for intravenous infusion, were phenotyped and analysed by flow cytometry. Significant differences in the subset ratios between the infused, starting population and the recirculated population indicated that CD4+ and gamma delta+T19+ lymphocytes are extracted by a resting lymph node at the same rate and that both are extracted at a faster rate than CD8+ lymphocytes. The results presented here also suggest that a unique subset of gamma delta+T19+ lymphocytes may be present in blood that does not recirculate through peripheral lymph nodes.

Animals↗