Biomedical subjects

Joseph Larkin

Publications and source records attributed to Joseph Larkin.

6 recordsLinked to original sources

PubMed2007

Activation of CD4+ CD25+ regulatory T cell suppressor function by analogs of the selecting peptide.

CD4+ CD25+ Foxp3+ regulatory T (Treg) cells can undergo both thymic selection and peripheral expansion in response to self peptides that are agonists for their T cell receptors (TCR). However, the specificity by which these TCR must recognize peptide:MHC complexes to activate Treg cell function is not known. We show that CD4+ CD25+ Foxp3+ Treg cells can mediate suppression in response to peptides that are only weakly cross-reactive with the self peptide that induced their formation in vivo. Moreover, suppression could be efficiently activated by peptide analogs that were inefficient at inducing CD69 up-regulation, and that also induced little or no proliferation of naïve CD4+ CD25- Foxp3- T cells expressing the same TCR. These findings provide evidence that self peptide-specific CD4+ CD25+ Foxp3+ Treg cells can exert regulatory function in response to self- and/or pathogen-derived peptides with which they are only weakly cross-reactive.

Animals↗

PubMed2006

Role of TCR specificity in CD4+ CD25+ regulatory T-cell selection.

CD4+ CD25+ regulatory T cells play a crucial role in preventing autoimmune disease and can also modulate immune responses in settings such as transplantation and infection. We have developed a transgenic mouse system in which the role that T-cell receptor (TCR) specificity for self-peptides plays in the formation of CD4+ CD25+ regulatory T cells can be examined. We have shown that interactions with a single self-peptide can induce thymocytes bearing an autoreactive TCR to undergo selection to become CD4+ CD25+ regulatory T cells and that thymocytes bearing TCRs with low affinity for the selecting peptide do not appear to undergo selection into this pathway. In addition, thymocytes with identical specificity for the selecting self-peptide can undergo overt deletion versus abundant selection to become CD4+ CD25+ regulatory T cells in response to variations in expression of the selecting peptide in different lineages of transgenic mice. Finally, we have shown that CD4+ CD25+ T cells proliferate in response to their selecting self-peptide in the periphery, but these cells do not proliferate in response to lymphopenia in the absence of the selecting self-peptide. These studies are determining how the specificity of the TCR for self-peptides directs the thymic selection and peripheral expansion of CD4+ CD25+ regulatory T cells.

Animals↗

PubMed2005

Positive and negative regulation of the IL-27 receptor during lymphoid cell activation.

Previous reports have focused on the ability of IL-27 to promote naive T cell responses but the present study reveals that surface expression of WSX-1, the ligand-specific component of the IL-27R, is low on these cells and that highest levels are found on effector and memory CD4(+) and CD8(+) T cells. Accordingly, during infection with Toxoplasma gondii, in vivo T cell activation is associated with enhanced expression of WSX-1, and, in vitro, TCR ligation can induce expression of WSX-1 regardless of the polarizing (Th1/Th2) environment present at the time of priming. However, while these data establish that mitogenic stimulation promotes expression of WSX-1 by T cells, activation of NK cells and NKT cells prompts a reduction in WSX-1 levels during acute toxoplasmosis. Together, with the finding that IL-2 can suppress expression of WSX-1 by activated CD4(+) T cells, these studies indicate that surface levels of the IL-27R can be regulated by positive and negative signals associated with lymphoid cell activation. Additionally, since high levels of WSX-1 are evident on resting NK cells, resting NKT cells, effector T cells, regulatory T cells, and memory T cells, the current work demonstrates that IL-27 can influence multiple effector cells of innate and adaptive immunity.

Animals↗

PubMed2004

CD4+ CD25+ regulatory T cell repertoire formation in response to varying expression of a neo-self-antigen.

We have examined the development of self-peptide-specific CD4+ CD25+ regulatory T cells in lineages of transgenic mice that express the influenza virus PR8 hemagglutinin (HA) under the control of several different promoters (HA transgenic mice). By mating these lineages with TS1-transgenic mice expressing a TCR that recognizes the major I-E(d)-restricted determinant from HA (site 1 (S1)), we show that S1-specific T cells undergo selection to become CD4+ CD25+ regulatory T cells in each of the lineages, although in varying numbers. In some lineages, S1-specific CD4+ CD25+ regulatory T cells are highly abundant; indeed, TS1xHA-transgenic mice can contain as many S1-specific CD4+ T cells as are present in TS1 mice, which do not express the neo-self HA. In another lineage, however, S1-specific thymocytes are subjected to more extensive deletion and far fewer S1-specific CD4+ CD25+ regulatory T cells accumulate in the periphery. We show that radioresistant stromal cells can direct both deletion and CD4+ CD25+ regulatory T cell selection of S1-specific thymocytes. Interestingly, even though their numbers can vary, the S1-specific CD4+ CD25+ regulatory T cells in all cases coexist with clonally related CD4+ CD25- T cells that lack regulatory function. These findings show that the formation of the CD4+ CD25+ regulatory T cell repertoire is sensitive to variations in the expression of self-peptides.

Animals↗

PubMed2004

CD4(+) CD25(+) regulatory T cell selection.

Accumulating evidence indicates that regulatory T cells play a crucial role in preventing autoimmunity. To examine the processes by which regulatory CD4(+) T cells are produced during immune repertoire formation, we have developed transgenic mice that express the influenza virus hemagglutinin (HA) and coexpress major histocompatibility complex class II-restricted T cell receptors (TCRs) with varying affinities for the HA-derived CD4(+) T cell determinant S1. We show that interactions with a single self-peptide can induce thymocytes bearing an autoreactive TCR to undergo selection to become CD4(+) CD25(+) regulatory T cells, and that thymocytes bearing TCRs with low affinity for S1 do not undergo selection into this pathway. We show that CD4(+) thymocytes with identical specificity for the S1 self-peptide can undergo overt deletion versus abundant selection to become CD4(+) CD25(+) regulatory T cells in response to variations in expression of the S1 self-peptide in different lineages of HA transgenic mice. We also show that CD4(+) CD25(+) T cells proliferate in response to their selecting self-peptide in the periphery. Moreover, they do not proliferate in response to lymphopenia in the absence of the selecting self-peptide, reflecting a low level of expression of the high-affinity receptor for IL-7 (CD127) relative to conventional CD4(+) T cells. These studies are determining how specificity for self-peptides directs the thymic selection and peripheral expansion of CD4(+) CD25(+) regulatory T cells. Moreover, the differing responsiveness of CD4(+) CD25(+) regulatory T cells to cytokine- versus self-peptide-mediated signals may direct their accumulation to sites where the self-peptide is expressed.

Animals↗

PubMed2003

Cutting edge: self-peptides drive the peripheral expansion of CD4+CD25+ regulatory T cells.

CD4(+)CD25(+) regulatory T cell selection is initiated by high-specificity interactions with self-peptides in the thymus, although how these cells respond to cytokine-derived signals and to re-exposure to self-peptide:MHC complexes in the periphery is not well understood. We have used a transgenic mouse system, in which the peptide that induces thymic selection of a clonal population of CD4(+)CD25(+) regulatory T cells is known, to show that CD4(+)CD25(+) T cells proliferate in response to their selecting self-peptide in vivo. Moreover, they do not proliferate in response to lymphopenia in the absence of the selecting self-peptide, reflecting a low level of expression of the high affinity receptor for IL-7 (CD127) relative to conventional CD4(+) T cells. That their selecting self-peptide is both required for and promotes the peripheral expansion of CD4(+)CD25(+) regulatory T cells may direct their accumulation in sites where the self-peptide is expressed.

Adoptive Transfer↗