Induction of IL-10 suppressors in lung transplant patients by CD4 +25+ regulatory T cells through CTLA-4 signaling

Ankit Bharat, Ryan C. Fields, Elbert P. Trulock, G. Alexander Patterson, Thalachallour Mohanakumar*

*Corresponding author for this work

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

T cell-mediated autoimmunity to collagen V (col-V), a sequestered yet immunogenic self-protein, can induce chronic lung allograft rejection in rodent models. In this study we characterized the role of CD4+CD25 + regulatory T cells (Tregs) in regulating col-V autoimmunity in human lung transplant (LT) recipients. LT recipients revealed a high frequency of col-V-reactive, IL-10-producing CD4+ T cells (TIL-10 cells) with low IL-2-, IFN-γ-, IL-5-, and no IL-4-producing T cells. These TIL-10 cells were distinct from Tregs because they lacked constitutive expression of both CD25 and Foxp3. Expansion of TIL-10 cells during col-V stimulation in vitro involved CTLA-4 on Tregs, because both depleting and blocking Tregs with anti-CTLA4 F(ab′)2 mAbs resulted in loss of TIL-10 cells with a concomitant increase in IFN-γ producing Th1 cells (TIFN-γ cells). A Transwell culture of col-V-specific TIL-10 cells with Th1 cells (those generated in absence of Tregs) from the same patient resulted in marked inhibition of IFN-γ and proliferation of TIFN-γ cells, which was reversed by neutralizing IL-10. Furthermore, the TIL-10 cells were HLA class II restricted because blocking HLA class II on APCs resulted in the loss of IL-10 production. Chronic lung allograft rejection was associated with the loss of Tregs with a concomitant decrease in TIL-10 cells and an increase in TIFN-γ cells. We conclude that LT patients have col-V-specific T cells that can be detected in the peripheral blood. The predominant col-V-specific T cells produce IL-10 that suppresses autoreactive Th1 cells independently of direct cellular contact. Tregs are pivotal for the induction of these "suppressor" TIL-10 cells.

Original languageEnglish (US)
Pages (from-to)5631-5638
Number of pages8
JournalJournal of Immunology
Volume177
Issue number8
DOIs
StatePublished - Oct 15 2006

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Regulatory T-Lymphocytes
Interleukin-10
T-Lymphocytes
Transplants
Lung
Collagen
Th1 Cells
Autoimmunity
Allografts
Interleukin-5
Interleukin-4
Interleukin-2
Rodentia
Cell Proliferation

ASJC Scopus subject areas

  • Immunology

Cite this

Bharat, Ankit ; Fields, Ryan C. ; Trulock, Elbert P. ; Patterson, G. Alexander ; Mohanakumar, Thalachallour. / Induction of IL-10 suppressors in lung transplant patients by CD4 +25+ regulatory T cells through CTLA-4 signaling. In: Journal of Immunology. 2006 ; Vol. 177, No. 8. pp. 5631-5638.
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abstract = "T cell-mediated autoimmunity to collagen V (col-V), a sequestered yet immunogenic self-protein, can induce chronic lung allograft rejection in rodent models. In this study we characterized the role of CD4+CD25 + regulatory T cells (Tregs) in regulating col-V autoimmunity in human lung transplant (LT) recipients. LT recipients revealed a high frequency of col-V-reactive, IL-10-producing CD4+ T cells (TIL-10 cells) with low IL-2-, IFN-γ-, IL-5-, and no IL-4-producing T cells. These TIL-10 cells were distinct from Tregs because they lacked constitutive expression of both CD25 and Foxp3. Expansion of TIL-10 cells during col-V stimulation in vitro involved CTLA-4 on Tregs, because both depleting and blocking Tregs with anti-CTLA4 F(ab′)2 mAbs resulted in loss of TIL-10 cells with a concomitant increase in IFN-γ producing Th1 cells (TIFN-γ cells). A Transwell culture of col-V-specific TIL-10 cells with Th1 cells (those generated in absence of Tregs) from the same patient resulted in marked inhibition of IFN-γ and proliferation of TIFN-γ cells, which was reversed by neutralizing IL-10. Furthermore, the TIL-10 cells were HLA class II restricted because blocking HLA class II on APCs resulted in the loss of IL-10 production. Chronic lung allograft rejection was associated with the loss of Tregs with a concomitant decrease in TIL-10 cells and an increase in TIFN-γ cells. We conclude that LT patients have col-V-specific T cells that can be detected in the peripheral blood. The predominant col-V-specific T cells produce IL-10 that suppresses autoreactive Th1 cells independently of direct cellular contact. Tregs are pivotal for the induction of these {"}suppressor{"} TIL-10 cells.",
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Induction of IL-10 suppressors in lung transplant patients by CD4 +25+ regulatory T cells through CTLA-4 signaling. / Bharat, Ankit; Fields, Ryan C.; Trulock, Elbert P.; Patterson, G. Alexander; Mohanakumar, Thalachallour.

In: Journal of Immunology, Vol. 177, No. 8, 15.10.2006, p. 5631-5638.

Research output: Contribution to journalArticle

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