Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-β
ABSTRACT To initiate an antileishmanial adaptive immune response, dendritic cells (DCs) must carry Leishmania antigens from peripheral tissues to local draining lymph nodes. However, the migratory capacity of DCs is largely compromised during Leishmania donovani infection. The molecular mechanism un...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2023-06-01
|
| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.04122-22 |
| _version_ | 1797803386025803776 |
|---|---|
| author | Manisha Yadav Md. Naushad Akhtar Manish Mishra Sandeep Kumar Raj Kumar Shubham Anil Nandal Pradip Sen |
| author_facet | Manisha Yadav Md. Naushad Akhtar Manish Mishra Sandeep Kumar Raj Kumar Shubham Anil Nandal Pradip Sen |
| author_sort | Manisha Yadav |
| collection | DOAJ |
| description | ABSTRACT To initiate an antileishmanial adaptive immune response, dendritic cells (DCs) must carry Leishmania antigens from peripheral tissues to local draining lymph nodes. However, the migratory capacity of DCs is largely compromised during Leishmania donovani infection. The molecular mechanism underlying this defective DC migration is not yet fully understood. Here, we demonstrate that L. donovani infection impaired the lymph node homing ability of DCs by decreasing C-type lectin receptor 2 (CLEC-2) expression. L. donovani exerted this inhibitory effect by inducing transforming growth factor-β (TGF-β) secretion from DCs. Indeed, TGF-β produced in this manner inhibited nuclear factor-κB (NF-κB)-mediated CLEC-2 expression on DCs by activating c-Src. Notably, suppression of c-Src expression significantly improved the arrival of DCs in draining lymph nodes by preventing L. donovani-induced CLEC-2 downregulation on DCs. These findings reveal a unique mechanism by which L. donovani inhibits DC migration to lymph nodes and suggest a key role for TGF-β, c-Src, and CLEC-2 in regulating this process. IMPORTANCE Dendritic cells (DCs) play a key role in initiating T cell-mediated protective immunity against visceral leishmaniasis (VL), the second most lethal parasitic disease in the world. However, the T cell-inducing ability of DCs critically depends on the extent of DC migration to regional lymph nodes. Notably, the migration of DCs is reported to be impaired during VL. The cause of this impaired DC migration, however, remains ill-defined. Here, we provide the first evidence that L. donovani, the causative agent of VL, attenuates the lymph node homing capacity of DCs by decreasing C-type lectin receptor 2 (CLEC-2) expression on DCs. Additionally, we have demonstrated how L. donovani mediates this inhibitory effect. Overall, our work has revealed a unique mechanism underlying L. donovani-induced impairment of DC migration and suggests a potential strategy to improve antileishmanial T cell activity by increasing DC arrival in lymph nodes. |
| first_indexed | 2024-03-13T05:21:09Z |
| format | Article |
| id | doaj.art-4c782ef57595446a8b63b27ff6f0444e |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-03-13T05:21:09Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-4c782ef57595446a8b63b27ff6f0444e2023-06-15T13:18:32ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-06-0111310.1128/spectrum.04122-22Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-βManisha Yadav0Md. Naushad Akhtar1Manish Mishra2Sandeep Kumar3Raj Kumar4Shubham5Anil Nandal6Pradip Sen7Division of Cell Biology and Immunology, Council of Scientific and Industrial Research—Institute of Microbial Technology, Chandigarh, IndiaDivision of Cell Biology and Immunology, Council of Scientific and Industrial Research—Institute of Microbial Technology, Chandigarh, IndiaDivision of Cell Biology and Immunology, Council of Scientific and Industrial Research—Institute of Microbial Technology, Chandigarh, IndiaDivision of Cell Biology and Immunology, Council of Scientific and Industrial Research—Institute of Microbial Technology, Chandigarh, IndiaDivision of Cell Biology and Immunology, Council of Scientific and Industrial Research—Institute of Microbial Technology, Chandigarh, IndiaDivision of Cell Biology and Immunology, Council of Scientific and Industrial Research—Institute of Microbial Technology, Chandigarh, IndiaDivision of Cell Biology and Immunology, Council of Scientific and Industrial Research—Institute of Microbial Technology, Chandigarh, IndiaDivision of Cell Biology and Immunology, Council of Scientific and Industrial Research—Institute of Microbial Technology, Chandigarh, IndiaABSTRACT To initiate an antileishmanial adaptive immune response, dendritic cells (DCs) must carry Leishmania antigens from peripheral tissues to local draining lymph nodes. However, the migratory capacity of DCs is largely compromised during Leishmania donovani infection. The molecular mechanism underlying this defective DC migration is not yet fully understood. Here, we demonstrate that L. donovani infection impaired the lymph node homing ability of DCs by decreasing C-type lectin receptor 2 (CLEC-2) expression. L. donovani exerted this inhibitory effect by inducing transforming growth factor-β (TGF-β) secretion from DCs. Indeed, TGF-β produced in this manner inhibited nuclear factor-κB (NF-κB)-mediated CLEC-2 expression on DCs by activating c-Src. Notably, suppression of c-Src expression significantly improved the arrival of DCs in draining lymph nodes by preventing L. donovani-induced CLEC-2 downregulation on DCs. These findings reveal a unique mechanism by which L. donovani inhibits DC migration to lymph nodes and suggest a key role for TGF-β, c-Src, and CLEC-2 in regulating this process. IMPORTANCE Dendritic cells (DCs) play a key role in initiating T cell-mediated protective immunity against visceral leishmaniasis (VL), the second most lethal parasitic disease in the world. However, the T cell-inducing ability of DCs critically depends on the extent of DC migration to regional lymph nodes. Notably, the migration of DCs is reported to be impaired during VL. The cause of this impaired DC migration, however, remains ill-defined. Here, we provide the first evidence that L. donovani, the causative agent of VL, attenuates the lymph node homing capacity of DCs by decreasing C-type lectin receptor 2 (CLEC-2) expression on DCs. Additionally, we have demonstrated how L. donovani mediates this inhibitory effect. Overall, our work has revealed a unique mechanism underlying L. donovani-induced impairment of DC migration and suggests a potential strategy to improve antileishmanial T cell activity by increasing DC arrival in lymph nodes.https://journals.asm.org/doi/10.1128/spectrum.04122-22dendritic cell traffickingCLEC-2Leishmania donovanic-SrcTGF-βNF-κB |
| spellingShingle | Manisha Yadav Md. Naushad Akhtar Manish Mishra Sandeep Kumar Raj Kumar Shubham Anil Nandal Pradip Sen Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-β Microbiology Spectrum dendritic cell trafficking CLEC-2 Leishmania donovani c-Src TGF-β NF-κB |
| title | Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-β |
| title_full | Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-β |
| title_fullStr | Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-β |
| title_full_unstemmed | Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-β |
| title_short | Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-β |
| title_sort | leishmania donovani attenuates dendritic cell trafficking to lymph nodes by inhibiting c type lectin receptor 2 expression via transforming growth factor β |
| topic | dendritic cell trafficking CLEC-2 Leishmania donovani c-Src TGF-β NF-κB |
| url | https://journals.asm.org/doi/10.1128/spectrum.04122-22 |
| work_keys_str_mv | AT manishayadav leishmaniadonovaniattenuatesdendriticcelltraffickingtolymphnodesbyinhibitingctypelectinreceptor2expressionviatransforminggrowthfactorb AT mdnaushadakhtar leishmaniadonovaniattenuatesdendriticcelltraffickingtolymphnodesbyinhibitingctypelectinreceptor2expressionviatransforminggrowthfactorb AT manishmishra leishmaniadonovaniattenuatesdendriticcelltraffickingtolymphnodesbyinhibitingctypelectinreceptor2expressionviatransforminggrowthfactorb AT sandeepkumar leishmaniadonovaniattenuatesdendriticcelltraffickingtolymphnodesbyinhibitingctypelectinreceptor2expressionviatransforminggrowthfactorb AT rajkumar leishmaniadonovaniattenuatesdendriticcelltraffickingtolymphnodesbyinhibitingctypelectinreceptor2expressionviatransforminggrowthfactorb AT shubham leishmaniadonovaniattenuatesdendriticcelltraffickingtolymphnodesbyinhibitingctypelectinreceptor2expressionviatransforminggrowthfactorb AT anilnandal leishmaniadonovaniattenuatesdendriticcelltraffickingtolymphnodesbyinhibitingctypelectinreceptor2expressionviatransforminggrowthfactorb AT pradipsen leishmaniadonovaniattenuatesdendriticcelltraffickingtolymphnodesbyinhibitingctypelectinreceptor2expressionviatransforminggrowthfactorb |