Species-specific CD4 ⁺ T cells enable prediction of mucosal immune phenotypes from microbiota composition

Abstract

How bacterial strains within a complex human microbiota collectively shape intestinal T cell homeostasis is not well understood. Methods that quickly identify effector strains or species that drive specific mucosal T cell phenotypes are needed to define general principles for how the microbiota modulates host immunity. We colonize germ-free mice with defined communities of cultured strains and profile antigen-specific responses directed toward individual strains ex vivo. We find that lamina propria T cells are specific to bacterial strains at the species level and can discriminate between strains of the same species. Ex vivo restimulations consistently identify the strains within complex communities that induce Th17 responses in vivo, providing the potential to shape baseline immune tone via community composition. Using an adoptive transfer model of colitis, we find that lamina propria T cells respond to different bacterial strains in conditions of inflammation versus homeostasis. Collectively, our approach represents a unique method for efficiently predicting the relative impact of individual bacterial strains within a complex community and for parsing microbiota-dependent phenotypes into component fractions.

Untangling the CD4 T cell response to the microbiota

“…In PNAS, Spindler et al. ( 4 ) tackle the diversity problem, and rather than focusing on a single microbe, the authors leverage defined complex microbial communities to better understand the rules governing the generation and composition of mucosal CD4 T cell responses.…”

“…To this effect, Spindler et al. ( 4 ) employ a clever in vitro T cell recall assay where T cells are first primed to respond to lysates of a specific bacterial strain in the presence of antigen-presenting cells and later restimulated with an array of different bacterial strain lysates in the presence of antigen-presenting cells to study the specificity and phenotype of the CD4 T cell response to the microbiota, with a particular focus on the T H 17 response, which is relevant given its role in maintaining the gut barrier ( 9 ). Importantly, the primary assumption in this system is that the T cell phenotype is shaped by the response to strain-specific peptides, although the requirement for specific peptide antigens is not explicitly tested and the role of nonpeptide bacterial ligands present in the lysate is not addressed.…”

“…In PNAS, Spindler et al. ( 4 ) demonstrate the applicability of a workflow allowing for the assessment of mucosal CD4 T cell responses against a complex community of microbes by combining in vivo community colonization experiments with the in vitro recall assay above to assess the nature of mucosal CD4 T cell responses generated in response to any given individual’s microbiota ( Fig. 1 A ).…”

“…Armed with this tool, Spindler et al. ( 4 ) were able to utilize the in vitro recall data to predict and subsequently validate which pool of microbes would or would not induce T H 17 cell responses in vivo upon colonization with these subcommunities. These results help move the field another step closer to the ultimate application of clinical microbiota interventions—designer microbiotas that will manipulate the immune tone in tissues of patients, with the aim of altering disease outcomes ( Fig.…”

“…The premise relies on data shown by Spindler et al. ( 4 ) that these in vitro stimulating microbes are capable of inducing the same T cell response in vivo in colonization experiments in mice. ( B ) The workflow presented in A allows for the characterization of donor communities and the identification of T H 17-inducing microbes (in red) in T H 17-high individuals (donor 1) that can be utilized in combination with known non-T H 17 inducers (donor 2) to create customized microbial communities with predictable in vivo mucosal CD4 T cell phenotypes.…”