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Maria Agustina Battistone, PhD, an Investigator in the Department of Nephrology at Massachusetts General Hospital and an Assistant Professor of Medicine at Harvard Medical School, is the senior author of a new study published in PNAS, Regulatory T cells play a crucial role in maintaining sperm tolerance and male fertility.

What was the question you set out to answer with this study?

How does the male reproductive tract (epididymis and testis) keep the inflammatory state under control for successful fertility?

What Methods or Approach Did You Use?

We used a cross-disciplinary approach that combined functional in vivo analyses, high-resolution confocal microscopy, ELISA assays, flow cytometry, and proteomic analyses, together with the use of an autoimmunity-induced mouse model, to comprehensively characterize the effects of immunotolerance loss in the reproductive organs and the development of severely impaired male immunological fertility.

What Did You Find?

We discovered that Regulatory T cells (typically keep immune cells from attacking healthy cells) maintain the inflammatory state under control in the male reproductive tract. The loss of this state induced uncontrolled inflammation and the development of antibodies that bind to spermatozoa causing a severe reduction in fertility.

What are the Clinical Implications?

The rate of human fertility has been declining worldwide, and many male infertility cases, which represent 50% of all infertility problems in couples, have no known cause, illustrating our poor knowledge of male reproductive biology.

This study fills knowledge gaps related to male reproductive biology and addresses crucial concepts of mucosal immunology and cell-cell interactions – all of which are critical, but understudied, facets of human male reproductive health, notably impacting sperm storage and their functional maturation.

The unraveling of these immunotolerance mechanisms involved in the maintenance of tissue homeostasis and inflammation represents a significant advancement in the understanding of not only immunological infertility but also different autoimmune diseases.

What are the Next Steps?

We are working with semen from idiopathic infertile patients to decipher if they have any immunological issues. For example, we are measuring anti-spermatozoa antibodies in these types of samples.

Paper cited:

Barrachina, F., Ottino, K., Elizagaray, M. L., Gervasi, M. G., Tu, L. J., Markoulaki, S., Spallanzani, R. G., Capen, D., Brown, D., & Battistone, M. A. (2023). Regulatory T cells play a crucial role in maintaining sperm tolerance and male fertility. Proceedings of the National Academy of Sciences of the United States of America, 120(37), e2306797120. https://doi.org/10.1073/pnas.2306797120

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.