Increased circulating Th17 cells and altered CD4 T cell maturation and differentiation in active tuberculosis with type 2 diabetes: a pilot study

Paul Ogongo^1*Yoscelina E Martinez-Lopez²Anthony Tran³Cecilia S Lindestam Arlehamn⁴Alessandro Sette⁵Ilse A Dominguez-Trejo²Lizette Garza⁶America M Cruz- Gonzalez⁷Raul Loera-Salazar⁸Javier E Rodríguez-Herrera⁸Genesis P Aguillón-Durán⁹Esperanza Milagros García-Oropesa¹⁰Joel D Ernst³Blanca I Restrepo²

• ¹School of Medicine, University of California San Francisco, San Francisco, United States
• ²The University of Texas Health Science Center at Houston School of Public Health, Houston, United States
• ³Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94110, USA, San Francisco, United States
• ⁴Department of Infectious Disease and Immunology, Center for Vaccine Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark, Copenhagen, Denmark
• ⁵La Jolla Institute for Immunology, San Diego, United States
• ⁶The University of Texas Rio Grande Valley Department of Health and Biomedical Sciences, Brownsville, United States
• ⁷Universidad Autonoma de Tamaulipas Facultad de Medicina e Ingenieria en Sistemas Computacionales, Matamoros, Mexico
• ⁸Universidad Tecnologica de Tamaulipas Norte, Reynosa, Mexico
• ⁹The University of Texas Health Science Center at San Antonio Department of Population Health Sciences, San Antonio, United States
• ¹⁰The University of Texas Rio Grande Valley School of Integrative Biological and Chemical Sciences Edinburg Campus, Edinburg, United States

Introduction Type 2 diabetes (T2D) is a major risk factor for developing tuberculosis (TB). However, understanding the role of defective T cell responses in T2D and TB has been difficult, largely due to inconsistencies across studies. These discrepancies often stem from T cell subset classification primarily relying on cytokine expression profiles, which may not fully capture the complexity of T cell maturation, differentiation, and function in TB patients with T2D. Objective and Methods In this pilot study, we sought to identify alterations in phenotypic and ex vivo responses of CD4 T cells to Mycobacterium tuberculosis (Mtb) antigens in people with TB with or without T2D. We evaluated peripheral blood mononuclear cells (PBMC) by high-parameter spectral flow cytometry and assessed T cell differentiation using a cytokine agnostic approach based on validated cell surface marker expression. Results We found major alterations in specific CD4 T cell properties by T2D status, despite no difference in the frequency of bulk CD4 or CD8 T cells. TB-T2D patients (vs TB alone) had fewer circulating naïve CD4 T cells, higher frequency CD4 T cell responses to Mtb antigens, and increased circulating Th1 and three subsets of Th17 cells. Multivariable analysis confirmed that T2D was independently associated with these alterations in maturation state, differentiation phenotype, and the activation of Mtb antigen-responsive CD4 T cells. Conclusion This pilot study reveals CD4 T cell alterations in T2D that likely worsen TB outcomes. A reduced naïve CD4 T cell pool, increased central memory and antigen-activated CD4 T cells, and elevated Th1 and three Th17 cell subsets suggest a pro-inflammatory environment favoring responses that may promote, rather than control TB. These findings highlight immune dysfunctions that could be targeted by host-directed therapies to prevent TB and improve outcomes in T2D patients.