During early human pregnancy, the fetal placenta implants into the uterine mucosa (decidua)where placental trophoblast cells intermingle and communicate with maternal cells. Trophoblastdecidual interactions underlie common diseases of pregnancy including pre-eclampsia and stillbirth. Here, we profile transcriptomes of ~70,000 single cells from first trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua reveals new subsets of perivascular and stromal cells, which are located in distinct decidual layers.There are three major subsets of decidual NK cells, with distinctive immunomodulatory and chemokine profiles. We develop a repository of ligand-receptor complexes (https://cellphonedb.org/) and a statistical tool to predict the cell-type specificity of cell-cell communication via these molecular interactions. This identifies many regulatory interactions that prevent any damaging innate or adaptive immune responses in this environment. Our single cell atlas of the maternal-fetal interface reveals the cellular organization and interactions critical for placentation and reproductive success.During early pregnancy, the uterine mucosal lining, the endometrium, is transformed into decidua under the influence of progesterone. Decidualisation results from a complex and well-orchestrated differentiation program that involves all cellular elements of the mucosa: stromal, glandular, and immune cells, including the distinctive decidual Natural Killer cells (dNK) 1,2 . The blastocyst implants into the decidua and initially, before arterial connections are established, uterine glands are the source of histotrophic nutrition in the placenta 3,4 . Following implantation, placental extravillous trophoblast cells (EVT) invade through the decidua and move towards the spiral arteries, where they destroy the smooth muscle media and transform the arteries into high conductance vessels 5 . Balanced regulation of EVT invasion is critical to pregnancy success: arteries must be sufficiently transformed, but excessive invasion prevented, to ensure correct allocation of resources to both mother and baby 6 . The pivotal regulatory role of the decidua is obvious from the life-threatening, uncontrolled, trophoblast invasion that occurs when the decidua is absent as when the placenta implants on a previous cesarean section scar 7 .EVT have a unique HLA profile: they do not express the dominant T cell ligands, class I HLA-A and HLA-B or class II molecules 8,9 , but do express HLA-G and HLA-E and polymorphic HLA-C class I molecules. These trophoblast HLA ligands have receptors expressed by the dominant decidual immune cells, dNK, including maternal killer immunoglobulin-like receptors (KIR), that bind HLA-C molecules 10,11 . Certain combinations of maternal KIR and fetal HLA-C genetic variants are associated with pregnancy disorders such as pre-eclampsia, where trophoblast invasion is deficient 12 . However, detailed understanding of the cellular interactions in the decidua supporting early...

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Key Points Clonal-like expansion of NK cells in response to CMV infection causes stable imprints in the human KIR repertoire. Education by inhibitory KIRs promotes the expansion of NK cells, causing repertoire skewing and a bias for self-specific inhibitory KIRs.

CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation.

Although NK cells are considered innate, recent studies in mice revealed the existence of a unique lineage of hepatic CD49a+DX5− NK cells with adaptive-like features. Development of this NK cell lineage is, in contrast to conventional NK cells, dependent on T-bet but not Eomes. In this study, we describe the identification of a T-bet+Eomes−CD49a+ NK cell subset readily detectable in the human liver, but not in afferent or efferent hepatic venous or peripheral blood. Human intrahepatic CD49a+ NK cells express killer cell Ig-like receptor and NKG2C, indicative of having undergone clonal-like expansion, are CD56bright, and express low levels of CD16, CD57, and perforin. After stimulation, CD49a+ NK cells express high levels of inflammatory cytokines but degranulate poorly. CD49a+ NK cells retain their phenotype after expansion in long-term in vitro cultures. These results demonstrate the presence of a likely human counterpart of mouse intrahepatic NK cells with adaptive-like features.

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Here, we characterize the major NK cell populations in the human lung. Our data suggest a model in which the majority of NK cells in the human lung dynamically move between blood and the lung rather than residing in the lung as bona fide tissue-resident CD69 NK cells.

The live attenuated yellow fever virus (YFV) 17D vaccine provides a good model to study immune responses to an acute viral infection in humans. We studied the temporal dynamics, composition, and character of the primary human T cell response to YFV. The acute YFV-specific effector CD8 T cell response was broad and complex; it was composed of dominant responses that persisted into the memory population, as well as of transient subdominant responses that were not detected at the memory stage. Furthermore, HLA-A2– and HLA-B7–restricted YFV epitope–specific effector cells predominantly displayed a CD45RA−CCR7−PD-1+CD27high phenotype, which transitioned into a CD45RA+CCR7−PD-1−CD27low memory population phenotype. The functional profile of the YFV-specific CD8 T cell response changed in composition as it matured from an effector- to a memory-type response, and it tended to become less polyfunctional during the course of this transition. Interestingly, activation of CD4 T cells, as well as FOXP3+ T regulatory cells, in response to YFV vaccination preceded the kinetics of the CD8 T cell response. The present results contribute to our understanding of how immunodominance patterns develop, as well as the phenotypic and functional characteristics of the primary human T cell response to a viral infection as it evolves and matures into memory.