Investigating the role of granzyme a in CD8 t cell exhaustion

The National Institute of Allergy and Infectious Diseases awarded Baylor College of Medicine $101,052 for basic research investigating the role of granzyme A in CD8 T cell exhaustion under the Allergy and Infectious Diseases Research program (CFDA 93.855) on October 16, 2026.

The funded research examines how CD8 T cells—which directly kill virally infected and cancerous cells—lose effector function when chronically stimulated by persistent antigens in chronic viral infections and cancer. The project focuses on understanding the mechanisms by which exhausted T cells express elevated levels of granzyme A and how this conversion from granzyme B in effector cells affects T cell differentiation and function. These findings aim to improve patient responses to immune checkpoint blockade immunotherapy by clarifying how progenitor exhausted T cells progress to intermediate cells with increased effector function and ultimately to terminally exhausted cells with diminished killing capacity.

Place of performance is Houston, Texas. The period of performance runs through April 19, 2030. This is a Project Grant assistance type.

Abstract

CD8 t cells directly mediate the specific killing of virally infected and cancerous cells. Upon recognizing a specific antigen presented on a target cell, t cells become activated and acquire effector function, including the secretion of perforins and granzymes to cause target cell death. However, when the antigen is not readily cleared, as in chronic viral infections and cancer, t cells enter a state of exhaustion where they express CO- inhibitory molecules like PD-1 and lose effector capacity. T cell exhaustion is a major contributor to the persistence of chronic viral infections and cancer. Inhibition of CD8 t cell CO-inhibitory pathways is the basis of immune checkpoint blockade (ICB), which reinvigorates t cell anti-tumor responses and can dramatically improve cancer outcomes. However, patient responses are variable, which can partially be attributed to the heterogeneity of exhausted t cell populations. ICB acts directly on a subset of exhausted t cells called progenitor cells, which expand and differentiate into intermediate cells, which have increased effector function. However, intermediate cells are short-lived and become terminally exhausted cells with low effector function. Understanding the mechanisms of differentiation from progenitor to terminal exhausted states will vastly improve patient responses to immunotherapy. Our group recently found that mouse and human exhausted t cells express high levels of granzyme a (gzma). Granzymes are a class of serine proteases that mediate target cell death, with granzymes a and b being the most abundant granzymes. While granzyme b (gzmb) is essential for t cell cytotoxicity and is reduced during exhaustion, little is known about the role of gzma. Our preliminary findings suggest a conversion from gzmb in effector t cells to gzma in exhausted t cells, but IT remains unknown how this process impacts the differentiation and function of exhausted t cells. We hypothesize that gzma expression is a compensatory mechanism in response to gzmb downregulation that functions to increase cytotoxic capacity during t cell exhaustion. We will mechanistically dissect the role of gzma in CD8 t cell exhaustion by generating a murine gzma-/- model and tracking t cell function during chronic viral infection and tumor progression. Aim 1 will use flow cytometry, single-cell RNA-sequencing, and functional assays to determine the CD8 t cell-intrinsic effects of gzma deletion during the longitudinal progression of t cell exhaustion during chronic viral infection. Aim 2 will test how gzma deletion impacts anti-tumor t cell function in the tumor microenvironment. Together, these aims will define the function of gzma in exhausted t cells and elucidate novel mechanisms in CD8 t cell exhaustion. The collaborative training environment, the cutting-edge core facilities, and the many experts in t cell immunology at baylor college of medicine and the texas medical center will strongly support the success of this project. The integrative training plan will comprehensively prepare the applicant for an academic physician- scientist career studying mechanisms of t cell biology to improve clinical outcomes for rheumatology patients.