MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4

Walsh, James T.; Hendrix, Sven; Boato, Francesco; Smirnov, Igor; Zheng, Jingjing; Lukens, John R.; Gadani, Sachin P.; Hechler, Daniel; Gölz, Greta; Rosenberger, Karen; Kammertöns, Thomas; Vogt, Johannes; Vogelaar, Christina Francisca; Siffrin, Volker; Radjavi, Ali; Fernández-Castañeda, Anthony; Gaultier, Alban; Gold, Ralf; Kanneganti, Thirumala‐Devi; Nitsch, Robert; Zipp, Frauke; Kipnis, Jonathan

doi:10.1172/jci76210

Cited by 160 publications

(125 citation statements)

References 47 publications

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“…MHCII is required for APC activation of and differentiation of CD4 + T cells, and MHCII -/-animals therefore lack both T cells and the ability to activate their TCR should they be introduced. As expected, MHCII -/-animals had impaired neuronal survival after optic nerve crush (Walsh et al, 2015). The critical experiment that tested the relevance of antigen specificity came in rescue experiments, where T cells are given to MHCII -/-animals.…”

Section: Lymphocytesmentioning

confidence: 62%

“…ILC2-derived IL-13 also works through DCs to recruit and potentiate memory Th2 responses (Halim, 2016). These findings frame ILC2s as critical players in Th2 differentiation, and connect them to recent work from our lab demonstrating that T cell derived IL-4 is neuroprotective after CNS injury (Walsh et al, 2015). Th2 cells enter the injury site and produce IL-4, which acts directly on neurons to promote neurotrophin production and survival (Walsh et al, 2015).…”

Section: A Working Hypothesis Of Meningeal Ilc2 Function In Health Anmentioning

confidence: 62%

“…as the likely signaling molecule (Walsh et al, 2015). Finally, we demonstrated in vitro that T cell derived IL-4 could be directly neuroprotective on neurons through neuronal IL-4R…”

Section: Lymphocytesmentioning

confidence: 74%

“…A similar trend seems to be emerging in CNS injury, though fewer studies are available on this topic. Results from our lab have shown impaired recovery after both spinal cord and optic nerve trauma in MyD88 -/-mice (Walsh et al, 2015). A 2007…”

Section: Prrs and Alarmins In Cns Injurymentioning

confidence: 96%

“…signaling, completing the antigen-independent mechanism of beneficial T cell activity (Walsh et al, 2015). IL-33 is a member of the IL-1 cytokine family along with IL-1β , IL-1α , and IL-18.…”

Section: Lymphocytesmentioning

confidence: 99%

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Interleukin 33 Initiates CNS Inflammation Following Traumatic Injury

Gadani¹

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Section: Lymphocytesmentioning

confidence: 62%

Section: A Working Hypothesis Of Meningeal Ilc2 Function In Health Anmentioning

confidence: 62%

“…as the likely signaling molecule (Walsh et al, 2015). Finally, we demonstrated in vitro that T cell derived IL-4 could be directly neuroprotective on neurons through neuronal IL-4R…”

Section: Lymphocytesmentioning

confidence: 74%

Section: Prrs and Alarmins In Cns Injurymentioning

confidence: 96%

Section: Lymphocytesmentioning

confidence: 99%

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Interleukin 33 Initiates CNS Inflammation Following Traumatic Injury

Gadani¹

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Improving thymus implantation for congenital athymia with interleukin‐7

Min,

Valente,

et al. 2023

Clin & Trans Imm

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ObjectivesThymus implantation is a recently FDA‐approved therapy for congenital athymia. Patients receiving thymus implantation develop a functional but incomplete T cell compartment. Our objective was to develop a mouse model to study clinical thymus implantation in congenital athymia and to optimise implantation procedures to maximise T cell education and expansion of naïve T cells.MethodsUsing Foxn1nu athymic mice as recipients, we tested MHC‐matched and ‐mismatched donor thymi that were implanted as fresh tissue or cultured to remove donor T cells. We first implanted thymus under the kidney capsule and then optimised intramuscular implantation. Using competitive adoptive transfer assays, we investigated whether the failure of newly developed T cells to expand into a complete T cell compartment was because of intrinsic deficits or whether there were deficits in engaging MHC molecules in the periphery. Finally, we tested whether recombinant IL‐7 would promote the expansion of host naïve T cells educated by the implanted thymus.ResultsWe determined that thymus implants in Foxn1nu athymic mice mimic many aspects of clinical thymus implants in patients with congenital athymia. When we implanted cultured, MHC‐mismatched donor thymus into Foxn1nu athymic mice, mice developed a limited T cell compartment with notably underdeveloped naïve populations and overrepresented memory‐like T cells. Newly generated T cells were predominantly educated by MHC molecules expressed by the donor thymus, thus potentially undergoing another round of selection once in the peripheral circulation. Using competitive adoptive transfer assays, we compared expansion rates of T cells educated on donor thymus versus T cells educated during typical thymopoiesis in MHC‐matched and ‐mismatched environments. Once in the circulation, regardless of the MHC haplotypes, T cells educated on a donor thymus underwent abnormal expansion with initially more robust proliferation coupled with greater cell death, resembling IL‐7 independent spontaneous expansion. Treating implanted mice with recombinant interleukin (IL‐7) promoted homeostatic expansion that improved T cell development, expanded the T cell receptor repertoire, and normalised the naïve T cell compartment.ConclusionWe conclude that implanting cultured thymus into the muscle of Foxn1nu athymic mice is an appropriate system to study thymus implantation for congenital athymia and immunodeficiencies. T cells are educated by the donor thymus, yet naïve T cells have deficits in expansion. IL‐7 greatly improves T cell development after thymus implantation and may offer a novel strategy to improve outcomes of clinical thymus implantation.

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