Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor
CD4+CD25+Foxp3+T cell population is heterogenous and contains three major sub-groups. First, thymus derived T regulatory cells (tTreg) that are naïve/resting. Second, activated/memory Treg that are produced by activation of tTreg by antigen and cytokines. Third, effector lineage CD4+CD25+T cells gen...
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| Format: | Article |
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.714838/full |
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| author | Bruce M. Hall Bruce M. Hall Rachael M. Hall Rachael M. Hall Giang T. Tran Giang T. Tran Catherine M. Robinson Catherine M. Robinson Paul L. Wilcox Paul L. Wilcox Prateek K. Rakesh Prateek K. Rakesh Chuanmin Wang Alexandra F. Sharland Nirupama D. Verma Nirupama D. Verma Suzanne J. Hodgkinson Suzanne J. Hodgkinson |
| author_facet | Bruce M. Hall Bruce M. Hall Rachael M. Hall Rachael M. Hall Giang T. Tran Giang T. Tran Catherine M. Robinson Catherine M. Robinson Paul L. Wilcox Paul L. Wilcox Prateek K. Rakesh Prateek K. Rakesh Chuanmin Wang Alexandra F. Sharland Nirupama D. Verma Nirupama D. Verma Suzanne J. Hodgkinson Suzanne J. Hodgkinson |
| author_sort | Bruce M. Hall |
| collection | DOAJ |
| description | CD4+CD25+Foxp3+T cell population is heterogenous and contains three major sub-groups. First, thymus derived T regulatory cells (tTreg) that are naïve/resting. Second, activated/memory Treg that are produced by activation of tTreg by antigen and cytokines. Third, effector lineage CD4+CD25+T cells generated from CD4+CD25- T cells’ activation by antigen to transiently express CD25 and Foxp3. We have shown that freshly isolated CD4+CD25+T cells are activated by specific alloantigen and IL-4, not IL-2, to Ts2 cells that express the IL-5 receptor alpha. Ts2 cells are more potent than naïve/resting tTreg in suppressing specific alloimmunity. Here, we showed rIL-5 promoted further activation of Ts2 cells to Th2-like Treg, that expressed foxp3, irf4, gata3 and il5. In vivo, we studied the effects of rIL-5 treatment on Lewis heart allograft survival in F344 rats. Host CD4+CD25+T cells were assessed by FACS, in mixed lymphocyte culture and by RT-PCR to examine mRNA of Ts2 or Th2-like Treg markers. rIL-5 treatment given 7 days after transplantation reduced the severity of rejection and all grafts survived ≥60d whereas sham treated rats fully rejected by day 31 (p<0.01). Treatment with anti-CD25 or anti-IL-4 monoclonal antibody abolished the benefits of treatment with rIL-5 and accelerated rejection. After 10d treatment with rIL-5, hosts’ CD4+CD25+ cells expressed more Il5ra and responded to specific donor Lewis but not self. Enriched CD4+CD25+ cells from rIL-5 treated rats with allografts surviving >60 days proliferated to specific donor only when rIL-5 was present and did not proliferate to self or third party. These cells had more mRNA for molecules expressed by Th2-like Treg including Irf4, gata3 and Il5. These findings were consistent with IL-5 treatment preventing rejection by activation of Ts2 cells and Th2-like Treg. |
| first_indexed | 2024-12-19T05:33:08Z |
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| id | doaj.art-886ca1e1c5ef4eb18f1eef7445395015 |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T05:33:08Z |
| publishDate | 2021-11-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-886ca1e1c5ef4eb18f1eef74453950152022-12-21T20:34:11ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-11-011210.3389/fimmu.2021.714838714838Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 ReceptorBruce M. Hall0Bruce M. Hall1Rachael M. Hall2Rachael M. Hall3Giang T. Tran4Giang T. Tran5Catherine M. Robinson6Catherine M. Robinson7Paul L. Wilcox8Paul L. Wilcox9Prateek K. Rakesh10Prateek K. Rakesh11Chuanmin Wang12Alexandra F. Sharland13Nirupama D. Verma14Nirupama D. Verma15Suzanne J. Hodgkinson16Suzanne J. Hodgkinson17Immune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, AustraliaIngham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, AustraliaImmune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, AustraliaIngham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, AustraliaImmune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, AustraliaIngham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, AustraliaImmune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, AustraliaIngham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, AustraliaImmune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, AustraliaIngham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, AustraliaImmune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, AustraliaIngham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, AustraliaTransplantation Immunobiology Group, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, AustraliaTransplantation Immunobiology Group, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, AustraliaImmune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, AustraliaIngham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, AustraliaImmune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, AustraliaIngham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, AustraliaCD4+CD25+Foxp3+T cell population is heterogenous and contains three major sub-groups. First, thymus derived T regulatory cells (tTreg) that are naïve/resting. Second, activated/memory Treg that are produced by activation of tTreg by antigen and cytokines. Third, effector lineage CD4+CD25+T cells generated from CD4+CD25- T cells’ activation by antigen to transiently express CD25 and Foxp3. We have shown that freshly isolated CD4+CD25+T cells are activated by specific alloantigen and IL-4, not IL-2, to Ts2 cells that express the IL-5 receptor alpha. Ts2 cells are more potent than naïve/resting tTreg in suppressing specific alloimmunity. Here, we showed rIL-5 promoted further activation of Ts2 cells to Th2-like Treg, that expressed foxp3, irf4, gata3 and il5. In vivo, we studied the effects of rIL-5 treatment on Lewis heart allograft survival in F344 rats. Host CD4+CD25+T cells were assessed by FACS, in mixed lymphocyte culture and by RT-PCR to examine mRNA of Ts2 or Th2-like Treg markers. rIL-5 treatment given 7 days after transplantation reduced the severity of rejection and all grafts survived ≥60d whereas sham treated rats fully rejected by day 31 (p<0.01). Treatment with anti-CD25 or anti-IL-4 monoclonal antibody abolished the benefits of treatment with rIL-5 and accelerated rejection. After 10d treatment with rIL-5, hosts’ CD4+CD25+ cells expressed more Il5ra and responded to specific donor Lewis but not self. Enriched CD4+CD25+ cells from rIL-5 treated rats with allografts surviving >60 days proliferated to specific donor only when rIL-5 was present and did not proliferate to self or third party. These cells had more mRNA for molecules expressed by Th2-like Treg including Irf4, gata3 and Il5. These findings were consistent with IL-5 treatment preventing rejection by activation of Ts2 cells and Th2-like Treg.https://www.frontiersin.org/articles/10.3389/fimmu.2021.714838/fullinterleukin-5transplant toleranceT regulatory cellscytokinesallograft rejectionchronic rejection |
| spellingShingle | Bruce M. Hall Bruce M. Hall Rachael M. Hall Rachael M. Hall Giang T. Tran Giang T. Tran Catherine M. Robinson Catherine M. Robinson Paul L. Wilcox Paul L. Wilcox Prateek K. Rakesh Prateek K. Rakesh Chuanmin Wang Alexandra F. Sharland Nirupama D. Verma Nirupama D. Verma Suzanne J. Hodgkinson Suzanne J. Hodgkinson Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor Frontiers in Immunology interleukin-5 transplant tolerance T regulatory cells cytokines allograft rejection chronic rejection |
| title | Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor |
| title_full | Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor |
| title_fullStr | Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor |
| title_full_unstemmed | Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor |
| title_short | Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor |
| title_sort | interleukin 5 il 5 therapy prevents allograft rejection by promoting cd4 cd25 ts2 regulatory cells that are antigen specific and express il 5 receptor |
| topic | interleukin-5 transplant tolerance T regulatory cells cytokines allograft rejection chronic rejection |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.714838/full |
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