Tertiary lymphoid structures support the development of allergen-specific progenitor CD4+ T cells

Area of Science:

• Immunology
• Cell Biology
• Respiratory Medicine

Background:

• Tissue-resident memory CD4+ T cells (T_RM) are crucial for adaptive immunity in non-lymphoid tissues.
• These cells mediate protective responses but also contribute to autoimmunity and allergic diseases.

Purpose of the Study:

• To investigate the heterogeneity of allergen-specific CD4+ T_RM in the lungs after house dust mite exposure.
• To elucidate the role of pulmonary tertiary lymphoid structures (TLS) in T_RM differentiation and function.

Main Methods:

• Transcriptional analysis and flow cytometry to profile CD4+ T_RM populations.
• Confocal and spatial transcriptomics to determine cell localization and transcriptional states.
• Experimental manipulation of TLS development and assessment of PD1 pathway signaling.

Main Results:

• Two distinct CD4+ T_RM populations were identified: a proinflammatory Th2 lineage and a progenitor TCF1+ lineage.
• Th2 cells were found in airways, while TCF1+ cells localized to TLS, indicating distinct anatomical niches.
• TLS were confirmed as progenitor niches, showing a transcriptional gradient from progenitor to Th2 cells along the TLS:airway axis.
• TLS development correlated with TCF1 expression, and TCF1+ cells within TLS responded to anti-PD1 treatment.

Conclusions:

• Pulmonary TLS serve as critical niches for progenitor CD4+ T_RM, driving the progression of chronic allergic inflammation.
• The PD1 pathway within TLS influences TCF1+ progenitor cells.
• Targeting TLS presents a potential therapeutic strategy for chronic inflammatory lung diseases.