Interleukins and Interleukin Receptors Evolutionary History and Origin in Relation to CD4+ T Cell Evolution
Understanding the evolution of interleukins and interleukin receptors is essential to control the function of CD4+ T cells in various pathologies. Numerous aspects of CD4+ T cells’ presence are controlled by interleukins including differentiation, proliferation, and plasticity. CD4+ T cells have eme...
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MDPI AG
2021-05-01
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| Online Access: | https://www.mdpi.com/2073-4425/12/6/813 |
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| author | Norwin Kubick Pavel Klimovich Patrick Henckell Flournoy Irmina Bieńkowska Marzena Łazarczyk Mariusz Sacharczuk Suniti Bhaumik Michel-Edwar Mickael Rajatava Basu |
| author_facet | Norwin Kubick Pavel Klimovich Patrick Henckell Flournoy Irmina Bieńkowska Marzena Łazarczyk Mariusz Sacharczuk Suniti Bhaumik Michel-Edwar Mickael Rajatava Basu |
| author_sort | Norwin Kubick |
| collection | DOAJ |
| description | Understanding the evolution of interleukins and interleukin receptors is essential to control the function of CD4+ T cells in various pathologies. Numerous aspects of CD4+ T cells’ presence are controlled by interleukins including differentiation, proliferation, and plasticity. CD4+ T cells have emerged during the divergence of jawed vertebrates. However, little is known about the evolution of interleukins and their origin. We traced the evolution of interleukins and their receptors from Placozoa to primates. We performed phylogenetic analysis, ancestral reconstruction, HH search, and positive selection analysis. Our results indicated that various interleukins’ emergence predated CD4+ T cells divergence. IL14 was the most ancient interleukin with homologs in fungi. Invertebrates also expressed various interleukins such as IL41 and IL16. Several interleukin receptors also appeared before CD4+ T cells divergence. Interestingly IL17RA and IL17RD, which are known to play a fundamental role in Th17 CD4+ T cells first appeared in mollusks. Furthermore, our investigations showed that there is not any single gene family that could be the parent group of interleukins. We postulate that several groups have diverged from older existing cytokines such as IL4 from TGFβ, IL10 from IFN, and IL28 from BCAM. Interleukin receptors were less divergent than interleukins. We found that IL1R, IL7R might have diverged from a common invertebrate protein that contained TIR domains, conversely, IL2R, IL4R and IL6R might have emerged from a common invertebrate ancestor that possessed a fibronectin domain. IL8R seems to be a GPCR that belongs to the rhodopsin-like family and it has diverged from the Somatostatin group. Interestingly, several interleukins that are known to perform a critical function for CD4+ T cells such as IL6, IL17, and IL1B have gained new functions and evolved under positive selection. Overall evolution of interleukin receptors was not under significant positive selection. Interestingly, eight interleukin families appeared in lampreys, however, only two of them (IL17B, IL17E) evolved under positive selection. This observation indicates that although lampreys have a unique adaptive immune system that lacks CD4+ T cells, they could be utilizing interleukins in homologous mode to that of the vertebrates’ immune system. Overall our study highlights the evolutionary heterogeneity within the interleukins and their receptor superfamilies and thus does not support the theory that interleukins evolved solely in jawed vertebrates to support T cell function. Conversely, some of the members are likely to play conserved functions in the innate immune system. |
| first_indexed | 2024-03-10T11:01:01Z |
| format | Article |
| id | doaj.art-f323aa0505d34b648675a45804ba212d |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T11:01:01Z |
| publishDate | 2021-05-01 |
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| spelling | doaj.art-f323aa0505d34b648675a45804ba212d2023-11-21T21:31:20ZengMDPI AGGenes2073-44252021-05-0112681310.3390/genes12060813Interleukins and Interleukin Receptors Evolutionary History and Origin in Relation to CD4+ T Cell EvolutionNorwin Kubick0Pavel Klimovich1Patrick Henckell Flournoy2Irmina Bieńkowska3Marzena Łazarczyk4Mariusz Sacharczuk5Suniti Bhaumik6Michel-Edwar Mickael7Rajatava Basu8Institute of Biochemistry, Molecular Cell Biology, University Clinic Hamburg-Eppendorf, 0251 Hamburg, GermanyPM Research Center, 20 Kaggeholm, Ekerö, 178 54 Stockholm, SwedenPM Research Center, 20 Kaggeholm, Ekerö, 178 54 Stockholm, SwedenInstitute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, ul. Postepu 36A, Jastrzebiec, 05-552 Magdalenka, PolandInstitute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, ul. Postepu 36A, Jastrzebiec, 05-552 Magdalenka, PolandInstitute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, ul. Postepu 36A, Jastrzebiec, 05-552 Magdalenka, PolandBevill Biomedical Sciences Research Building, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USAPM Research Center, 20 Kaggeholm, Ekerö, 178 54 Stockholm, SwedenBevill Biomedical Sciences Research Building, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USAUnderstanding the evolution of interleukins and interleukin receptors is essential to control the function of CD4+ T cells in various pathologies. Numerous aspects of CD4+ T cells’ presence are controlled by interleukins including differentiation, proliferation, and plasticity. CD4+ T cells have emerged during the divergence of jawed vertebrates. However, little is known about the evolution of interleukins and their origin. We traced the evolution of interleukins and their receptors from Placozoa to primates. We performed phylogenetic analysis, ancestral reconstruction, HH search, and positive selection analysis. Our results indicated that various interleukins’ emergence predated CD4+ T cells divergence. IL14 was the most ancient interleukin with homologs in fungi. Invertebrates also expressed various interleukins such as IL41 and IL16. Several interleukin receptors also appeared before CD4+ T cells divergence. Interestingly IL17RA and IL17RD, which are known to play a fundamental role in Th17 CD4+ T cells first appeared in mollusks. Furthermore, our investigations showed that there is not any single gene family that could be the parent group of interleukins. We postulate that several groups have diverged from older existing cytokines such as IL4 from TGFβ, IL10 from IFN, and IL28 from BCAM. Interleukin receptors were less divergent than interleukins. We found that IL1R, IL7R might have diverged from a common invertebrate protein that contained TIR domains, conversely, IL2R, IL4R and IL6R might have emerged from a common invertebrate ancestor that possessed a fibronectin domain. IL8R seems to be a GPCR that belongs to the rhodopsin-like family and it has diverged from the Somatostatin group. Interestingly, several interleukins that are known to perform a critical function for CD4+ T cells such as IL6, IL17, and IL1B have gained new functions and evolved under positive selection. Overall evolution of interleukin receptors was not under significant positive selection. Interestingly, eight interleukin families appeared in lampreys, however, only two of them (IL17B, IL17E) evolved under positive selection. This observation indicates that although lampreys have a unique adaptive immune system that lacks CD4+ T cells, they could be utilizing interleukins in homologous mode to that of the vertebrates’ immune system. Overall our study highlights the evolutionary heterogeneity within the interleukins and their receptor superfamilies and thus does not support the theory that interleukins evolved solely in jawed vertebrates to support T cell function. Conversely, some of the members are likely to play conserved functions in the innate immune system.https://www.mdpi.com/2073-4425/12/6/813interleukinsCD4+ T cellsevolutionTh17 |
| spellingShingle | Norwin Kubick Pavel Klimovich Patrick Henckell Flournoy Irmina Bieńkowska Marzena Łazarczyk Mariusz Sacharczuk Suniti Bhaumik Michel-Edwar Mickael Rajatava Basu Interleukins and Interleukin Receptors Evolutionary History and Origin in Relation to CD4+ T Cell Evolution Genes interleukins CD4+ T cells evolution Th17 |
| title | Interleukins and Interleukin Receptors Evolutionary History and Origin in Relation to CD4+ T Cell Evolution |
| title_full | Interleukins and Interleukin Receptors Evolutionary History and Origin in Relation to CD4+ T Cell Evolution |
| title_fullStr | Interleukins and Interleukin Receptors Evolutionary History and Origin in Relation to CD4+ T Cell Evolution |
| title_full_unstemmed | Interleukins and Interleukin Receptors Evolutionary History and Origin in Relation to CD4+ T Cell Evolution |
| title_short | Interleukins and Interleukin Receptors Evolutionary History and Origin in Relation to CD4+ T Cell Evolution |
| title_sort | interleukins and interleukin receptors evolutionary history and origin in relation to cd4 t cell evolution |
| topic | interleukins CD4+ T cells evolution Th17 |
| url | https://www.mdpi.com/2073-4425/12/6/813 |
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