Bcl11b sustains multipotency and restricts effector programs of intestinal-resident memory CD8⁺ T cells

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• The transcription factors (TFs) governing intestinal-resident memory CD8+ T (T_RM) cell differentiation and function are not fully understood.
• Understanding these regulatory networks is crucial for developing effective immune strategies against intestinal pathogens.

Purpose of the Study:

• To investigate the role of the transcription factor Bcl11b in the development and function of intestinal T_RM cells.
• To elucidate how Bcl11b influences the multipotency and effector programs of these cells during infection.

Main Methods:

• Conditional deletion of Bcl11b in CD8+ T cells in mice post-activation.
• Infection with *Listeria monocytogenes*.
• Analysis of T cell populations in spleen and intestine, including transcriptional and epigenetic profiling.

Main Results:

• Conditional deletion of Bcl11b led to increased intestinal T_RM cells but decreased splenic effector and circulating memory cells.
• Bcl11b-deficient T_RM cells showed diminished multipotency/multifunctional (MP/MF) gene expression (e.g., *Tcf7*) and increased effector gene expression (e.g., *Prdm1*).
• Epigenetic changes, including reduced chromatin accessibility and activating histone marks, were observed at MP/MF gene loci in Bcl11b-deficient cells.

Conclusions:

• Bcl11b acts as a key regulator of intestinal T_RM cell programming, promoting multipotency and limiting effector differentiation.
• Bcl11b functions upstream of Tcf1 and Blimp1 in controlling tissue residency programs.
• Dysregulation of Bcl11b impacts T_RM cell function, leading to impaired recall responses despite increased cell numbers.