Renal Operational Tolerance Is Associated With a Defect of Blood Tfh Cells That Exhibit Impaired B Cell Help

Area of Science:

• Immunology
• Transplantation immunology
• Cellular immunology

Background:

• Operational tolerance (TOL) in renal transplant recipients is characterized by impaired B cell differentiation and plasma cell deficiency.
• T follicular helper (Tfh) cells are crucial for B cell differentiation and antibody production.
• Understanding Tfh cell function in TOL is vital for elucidating immune tolerance mechanisms.

Purpose of the Study:

• To analyze Tfh cell subsets and function in renal operationally tolerant (TOL) patients compared to stable (STA) transplant recipients.
• To investigate the relationship between Tfh cell defects and the incidence of de novo donor-specific antibodies (dnDSA) in TOL patients.
• To explore the potential predictive role of Tfh cells in the development of dnDSA.

Main Methods:

• Analysis of Tfh cell subsets in the blood of TOL and STA patients.
• Functional assessment of Tfh cells, including gene expression profiling and cytokine production (interleukin-21).
• Evaluation of Tfh cell capacity to induce IgG production by naive B cells.

Main Results:

• TOL patients exhibited a reduced proportion of activated and functional blood Tfh subsets, with normal absolute Tfh cell numbers.
• Tfh cells from TOL patients showed altered gene expression, failed to produce interleukin-21, and could not induce IgG production in naive B cells.
• A defect in Tfh cells in TOL was associated with a lower incidence of dnDSA, suggesting a protolerogenic environment.

Conclusions:

• Impaired Tfh cell function and disrupted homeostasis in TOL patients contribute to a reduced risk of developing dnDSA.
• Blood Tfh cell levels may serve as a predictive marker for dnDSA occurrence in transplant recipients.
• These findings offer new insights into the mechanisms underlying antibody responses and tolerance in transplantation.