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1.
Nature ; 610(7930): 161-172, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36171284

RESUMEN

Expansion and differentiation of antigen-experienced PD-1+TCF-1+ stem-like CD8+ T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade1-4. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of 'better effector' CD8+ T cells similar to those generated in an acute infection5. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor ß- and γ-chain (IL-2Rßγ)-biased agonists are currently being developed6-10. Here we show that IL-2Rßγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rßγ on the same cell recovers the ability to differentiate stem-like CD8+ T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.


Asunto(s)
Linfocitos T CD8-positivos , Receptor de Muerte Celular Programada 1 , Receptores de Interleucina-2 , Anticuerpos Bloqueadores/inmunología , Anticuerpos Bloqueadores/farmacología , Anticuerpos Bloqueadores/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Infecciones/tratamiento farmacológico , Infecciones/inmunología , Interleucina-2/inmunología , Interleucina-2/farmacología , Interleucina-2/uso terapéutico , Subunidad alfa del Receptor de Interleucina-2/agonistas , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptores de Interleucina-2/agonistas
2.
PLoS Pathog ; 14(5): e1007069, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29782555

RESUMEN

The opportunistic fungal pathogen Candida albicans frequently causes diseases such as oropharyngeal candidiasis (OPC) in immunocompromised individuals. Although it is well appreciated that the cytokine IL-17 is crucial for protective immunity against OPC, the cellular source and the regulation of this cytokine during infection are still a matter of debate. Here, we directly visualized IL-17 production in the tongue of experimentally infected mice, thereby demonstrating that this key cytokine is expressed by three complementary subsets of CD90+ leukocytes: RAG-dependent αß and γδ T cells, as well as RAG-independent ILCs. To determine the regulation of IL-17 production at the onset of OPC, we investigated in detail the myeloid compartment of the tongue and found a heterogeneous and dynamic mononuclear phagocyte (MNP) network in the infected tongue that consists of Zbtb46-Langerin- macrophages, Zbtb46+Langerin+ dendritic cells (DCs) and Ly6C+ inflammatory monocytes. Of those, the Langerin+ DC population stands out by its unique capacity to co-produce the cytokines IL-1ß, IL-6 and IL-23, all of which promote IL-17 induction in response to C. albicans in the oral mucosa. The critical role of Langerin+ DCs for the innate IL-17 response was confirmed by depletion of this cellular subset in vivo, which compromised IL-17 induction during OPC. In conclusion, our work revealed key regulatory factors and their cellular sources of innate IL-17-dependent antifungal immunity in the oral mucosa.


Asunto(s)
Antígenos de Superficie/inmunología , Candida albicans/inmunología , Candidiasis Bucal/inmunología , Células Dendríticas/inmunología , Interleucina-17/biosíntesis , Lectinas Tipo C/inmunología , Lectinas de Unión a Manosa/inmunología , Mucosa Bucal/inmunología , Animales , Candidiasis Bucal/microbiología , Citocinas/inmunología , Femenino , Citometría de Flujo , Interleucina-1beta/biosíntesis , Interleucina-23/biosíntesis , Interleucina-23/inmunología , Interleucina-6/biosíntesis , Leucocitos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Sistema Mononuclear Fagocítico/inmunología , Mucosa Bucal/citología , Mucosa Bucal/microbiología , Neutrófilos/inmunología , Organismos Libres de Patógenos Específicos , Bazo/citología , Bazo/inmunología , Antígenos Thy-1/inmunología , Lengua/citología , Lengua/inmunología , Lengua/microbiología
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