RESUMO
Foxp3+ T regulatory (Treg) cells promote immunological tumor tolerance, but how their immune-suppressive function is regulated in the tumor microenvironment (TME) remains unknown. Here, we used intravital microscopy to characterize the cellular interactions that provide tumor-infiltrating Treg cells with critical activation signals. We found that the polyclonal Treg cell repertoire is pre-enriched to recognize antigens presented by tumor-associated conventional dendritic cells (cDCs). Unstable cDC contacts sufficed to sustain Treg cell function, whereas T helper cells were activated during stable interactions. Contact instability resulted from CTLA-4-dependent downregulation of co-stimulatory B7-family proteins on cDCs, mediated by Treg cells themselves. CTLA-4-blockade triggered CD28-dependent Treg cell hyper-proliferation in the TME, and concomitant Treg cell inactivation was required to achieve tumor rejection. Therefore, Treg cells self-regulate through a CTLA-4- and CD28-dependent feedback loop that adjusts their population size to the amount of local co-stimulation. Its disruption through CTLA-4-blockade may off-set therapeutic benefits in cancer patients.
Assuntos
Antígeno CTLA-4/metabolismo , Retroalimentação Fisiológica , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos CD28/metabolismo , Proliferação de Células , Células Dendríticas/imunologia , Proteínas de Fluorescência Verde/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Interleucina-2/metabolismo , Ligantes , Linfonodos/metabolismo , Ativação Linfocitária/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Microambiente TumoralRESUMO
Recent guidance from the US Immigration and Customs Enforcement drastically altered the lives of international students in America, especially those who are matriculating. This commentary describes how international students still face uncertainty concerning their visa statuses and their place in American society.
