Thymus-derived myeloid programs track microglial tolerance states across human cohorts

Area of Science:

• Neuroimmunology
• Single-cell transcriptomics
• Human Cohort Studies

Background:

• Microglial positioning varies, hindering reproducible cross-cohort studies.
• T cell development uses chemokines, ECM factors, and axon guidance cues.
• Investigating thymus-derived programs for microglial positioning.

Purpose of the Study:

• To determine if thymus-derived transcriptional programs can quantify microglial tolerance-like positioning.
• To assess the transferability of these programs across independent human cohorts.

Main Methods:

• Applied consensus non-negative matrix factorization to thymus single-cell transcriptomes to derive Myeloid Education Signatures (MES).
• Projected MES scores into four independent microglia cohorts and related them to a donor-level tolerance score.
• Evaluated glucocorticoid receptor (GR) activity as a moderator using meta-analysis.

Main Results:

• Seven of eight MES modules inversely associated with microglial tolerance positioning.
• Thymus-derived modules showed stronger coupling to microglial positioning than modules from other tissues.
• Glucocorticoid receptor activity did not significantly moderate the observed association.

Conclusions:

• Thymus-derived myeloid programs represent a transferable, tissue-preferential axis.
• This axis is inversely coupled to microglial tolerance-like positioning.
• No detectable glucocorticoid moderation of this coupling was observed.