CCR4 and CCR7 differentially regulate thymocyte localization with distinct outcomes for central tolerance

Area of Science:

• Immunology
• T cell biology
• Autoimmunity

Background:

• Central tolerance is crucial for preventing autoimmunity by eliminating self-reactive T cells in the thymus.
• Thymocytes migrate to the medulla to encounter self-antigens presented by antigen-presenting cells (APCs) for negative selection.
• The roles of chemokine receptors CCR4 and CCR7 in this process are not fully understood, with potential for distinct or redundant functions.

Purpose of the Study:

• To investigate the specific roles of CCR4 and CCR7 in thymocyte medullary entry and central tolerance.
• To determine if CCR4 and CCR7 act distinctly or redundantly in the negative selection of T cells.
• To elucidate the temporal and functional differences between CCR4 and CCR7 in central tolerance.

Main Methods:

• Synchronized positive selection assays in mice.
• Two-photon time-lapse microscopy of thymocytes.
• Quantification of T-cell receptor (TCR)-signaled apoptotic thymocytes.

Main Results:

• CCR4 and CCR7 differentially regulate medullary accumulation and central tolerance of distinct post-positive selection thymocyte subsets.
• CCR4 promotes early medullary entry and deletion of immature thymocytes hours after positive selection.
• CCR7 facilitates later medullary localization and negative selection of mature thymocytes, days after positive selection.

Conclusions:

• CCR4 and CCR7 play distinct, non-redundant roles in central tolerance, acting at different developmental stages.
• CCR4 mediates tolerance to self-antigens presented by activated APCs, while CCR7 is required for mature thymocyte selection.
• CCR7 expression is not solely indicative of medullary localization, and a revised model of central tolerance involving distinct APC interactions is proposed.