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Requirement of cognate CD4+ T-cell recognition for the regulation of allospecific CTL by human CD4+ CD127- CD25+ FOXP3+ cells generated in MLR.

Publication ,  Journal Article
Yu, Y; Miller, J; Leventhal, JR; Tambur, AR; Chandrasekaran, D; Levitsky, J; Luo, X; Mathew, JM
Published in: PLoS One
2011

Although immunoregulation of alloreactive human CTLs has been described, the direct influence of CD4(+) Tregs on CD8(+) cytotoxicity and the interactive mechanisms have not been well clarified. Therefore, human CD4(+)CD127(-)CD25(+)FOXP3(+) Tregs were generated in MLR, immunoselected and their allospecific regulatory functions and associated mechanisms were then tested using modified (51)Chromium release assays (Micro-CML), MLRs and CFSE-based multi-fluorochrome flow cytometry proliferation assays. It was observed that increased numbers of CD4(+)CD127(-)CD25(+)FOXP3(+) cells were generated after a 7 day MLR. After immunoselection for CD4(+)CD127(-)CD25(+) cells, they were designated as MLR-Tregs. When added as third component modulators, MLR-Tregs inhibited the alloreactive proliferation of autologous PBMC in a concentration dependent manner. The inhibition was quasi-antigen specific, in that the inhibition was non-specific at higher MLR-Treg modulator doses, but non-specificity disappeared with lower numbers at which specific inhibition was still significant. When tested in micro-CML assays CTL inhibition occurred with PBMC and purified CD8(+) responders. However, antigen specificity of CTL inhibition was observed only with unpurified PBMC responders and not with purified CD8(+) responders or even with CD8(+) responders plus Non-T "APC". However, allospecificity of CTL regulation was restored when autologous purified CD4(+) T cells were added to the CD8(+) responders. Proliferation of CD8(+) cells was suppressed by MLR-Tregs in the presence or absence of IL-2. Inhibition by MLR-Tregs was mediated through down-regulation of intracellular perforin, granzyme B and membrane-bound CD25 molecules on the responding CD8(+) cells. Therefore, it was concluded that human CD4(+)CD127(-)CD25(+)FOXP3(+) MLR-Tregs down-regulate alloreactive cytotoxic responses. Regulatory allospecificity, however, requires the presence of cognate responding CD4(+) T cells. CD8(+) CTL regulatory mechanisms include impaired proliferation, reduced expression of cytolytic molecules and CD25(+) activation epitopes.

Duke Scholars

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2011

Volume

6

Issue

7

Start / End Page

e22450

Location

United States

Related Subject Headings

  • T-Lymphocytes, Regulatory
  • T-Lymphocytes, Cytotoxic
  • Lymphocyte Culture Test, Mixed
  • Interleukin-7 Receptor alpha Subunit
  • Interleukin-2 Receptor alpha Subunit
  • Humans
  • General Science & Technology
  • Forkhead Transcription Factors
  • Cell Differentiation
  • CD4 Antigens
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Yu, Y., Miller, J., Leventhal, J. R., Tambur, A. R., Chandrasekaran, D., Levitsky, J., … Mathew, J. M. (2011). Requirement of cognate CD4+ T-cell recognition for the regulation of allospecific CTL by human CD4+ CD127- CD25+ FOXP3+ cells generated in MLR. PLoS One, 6(7), e22450. https://doi.org/10.1371/journal.pone.0022450
Yu, Yuming, Joshua Miller, Joseph R. Leventhal, Anat R. Tambur, Dhivya Chandrasekaran, Josh Levitsky, Xunrong Luo, and James M. Mathew. “Requirement of cognate CD4+ T-cell recognition for the regulation of allospecific CTL by human CD4+ CD127- CD25+ FOXP3+ cells generated in MLR.PLoS One 6, no. 7 (2011): e22450. https://doi.org/10.1371/journal.pone.0022450.
Yu Y, Miller J, Leventhal JR, Tambur AR, Chandrasekaran D, Levitsky J, et al. Requirement of cognate CD4+ T-cell recognition for the regulation of allospecific CTL by human CD4+ CD127- CD25+ FOXP3+ cells generated in MLR. PLoS One. 2011;6(7):e22450.
Yu, Yuming, et al. “Requirement of cognate CD4+ T-cell recognition for the regulation of allospecific CTL by human CD4+ CD127- CD25+ FOXP3+ cells generated in MLR.PLoS One, vol. 6, no. 7, 2011, p. e22450. Pubmed, doi:10.1371/journal.pone.0022450.
Yu Y, Miller J, Leventhal JR, Tambur AR, Chandrasekaran D, Levitsky J, Luo X, Mathew JM. Requirement of cognate CD4+ T-cell recognition for the regulation of allospecific CTL by human CD4+ CD127- CD25+ FOXP3+ cells generated in MLR. PLoS One. 2011;6(7):e22450.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2011

Volume

6

Issue

7

Start / End Page

e22450

Location

United States

Related Subject Headings

  • T-Lymphocytes, Regulatory
  • T-Lymphocytes, Cytotoxic
  • Lymphocyte Culture Test, Mixed
  • Interleukin-7 Receptor alpha Subunit
  • Interleukin-2 Receptor alpha Subunit
  • Humans
  • General Science & Technology
  • Forkhead Transcription Factors
  • Cell Differentiation
  • CD4 Antigens