RESUMO
The current model of murine innate lymphoid cell (ILC) development holds that mouse ILCs are derived downstream of the common lymphoid progenitor through lineage-restricted progenitors. However, corresponding lineage-restricted progenitors in humans have yet to be discovered. Here we identified a progenitor population in human secondary lymphoid tissues (SLTs) that expressed the transcription factor RORγt and was unique in its ability to generate all known ILC subsets, including natural killer (NK) cells, but not other leukocyte populations. In contrast to murine fate-mapping data, which indicate that only ILC3s express Rorγt, these human progenitor cells as well as human peripheral blood NK cells and all mature ILC populations expressed RORγt. Thus, all human ILCs can be generated through an RORγt(+) developmental pathway from a common progenitor in SLTs. These findings help establish the developmental signals and pathways involved in human ILC development.
Assuntos
Células Matadoras Naturais/fisiologia , Linfonodos/imunologia , Subpopulações de Linfócitos/fisiologia , Células Progenitoras Linfoides/fisiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Tonsila Palatina/imunologia , Adulto , Animais , Antígenos CD34/metabolismo , Diferenciação Celular , Linhagem Celular , Criança , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genéticaRESUMO
Human natural killer (NK) cells develop in secondary lymphoid tissues (SLTs) through distinct stages. We identified two SLT lineage (Lin)(-)CD34(-)CD117(+/-)CD94(+)CD16(-) "stage 4" subsets according to expression of the C-type lectin-like surface-activating receptor, NKp80: NKp80(-) (stage "4a") and NKp80(+) (stage "4b"). Whereas stage 4b cells expressed more of the transcription factors T-BET and EOMES, produced interferon-gamma, and were cytotoxic, stage 4a cells expressed more of the transcription factors RORγt and AHR and produced interleukin-22, similar to SLT Lin(-)CD34(-)CD117(+)CD94(-)CD16(-) "stage 3" cells, whose phenotype overlaps with that of group 3 innate lymphoid cells (ILC3s). Co-culture with dendritic cells or transplantation into immunodeficient mice produced mature NK cells from stage 3 and stage 4a populations. These data identify NKp80 as a marker of NK cell maturity in SLTs and support a model of human NK cell development through a stage 4a intermediate with ILC3-associated features.
Assuntos
Células Matadoras Naturais/fisiologia , Lectinas Tipo C/metabolismo , Receptores de Células Matadoras Naturais/metabolismo , Animais , Células Cultivadas , Células Dendríticas/fisiologia , Feminino , Humanos , Células Matadoras Naturais/transplante , Tecido Linfoide/citologia , Camundongos Endogâmicos NOD , Camundongos SCIDRESUMO
We have developed a rapid negative selection method to enrich rare mononuclear cells from human tissues. Unwanted and antibody-tethered cells are selectively depleted during a Ficoll separation step, and there is no need for magnetic-based reagents and equipment. The new method is fast, customizable, inexpensive, remarkably efficient, and easy to perform, and per sample the overall cost is less than one-tenth the cost associated with a magnetic column-based method.