Heterogeneity in immune responses: from populations to single cells

• Diversity in the immune system is encoded by extensive cellular variation.
• Heterogeneity exists at multiple molecular levels.
• New single cell methods enable systematic studies of heterogeneity.
• A fundamental challenge is to connect molecular variability with phenotypic diversity.

The mammalian immune system is tasked with protecting the host against a broad range of threats. Understanding how immune populations leverage cellular diversity to achieve this breadth and flexibility, particularly during dynamic processes such as differentiation and antigenic response, is a core challenge that is well suited for single cell analysis. Recent years have witnessed transformative and intersecting advances in nanofabrication and genomics that enable deep profiling of individual cells, affording exciting opportunities to study heterogeneity in the immune response at an unprecedented scope. In light of these advances, here we review recent work exploring how immune populations generate and leverage cellular heterogeneity at multiple molecular and phenotypic levels. Additionally, we highlight opportunities for single cell technologies to shed light on the causes and consequences of heterogeneity in the immune system.