Does T cell Exhaustion occur in pregnant women with chronic Toxoplasma gondii infection?

We have recently reported finding significantly suppressed levels of inflammatory cytokines, IFN- γ , IL-6, IL-17, and IL-12 across pregnancy in women with T.gondii (TG) chronic infection (n=158) (Prescott S, et al. (2023). A mechanism that may be related to the reduced cytokines in latent infection is T cell exhaustion due to lifelong exposure of the immune system to parasite antigens. Latent, persistent, infections may continuously provide antigen exposure to T cell receptors (TCRs), leading to exhaustion of TCRs on antigen specific T cells. Pregnancy related fetal antigen exposure at the placenta also can produce T cell exhaustion. T cell exhaustion is marked by increased expression of inhibitory receptors on CD8 cells, loss of the ability to secrete cytokines, and development of different transcriptional programs. Exhaustion progresses over the time of continuous antigen exposure and is marked by cell signature immune checkpoint molecules. The cells most affected are the CD8 effector cells, which, in the case of TG, produce the proinflammatory milieu suppressing bradyzoite cysts. A loss of these CD8 effectors allows for the loss of memory responses to the antigens. Our data also suggested TG associated significant suppressed activation of the indoleamine 2,3-dioxygenase (IDO) enzyme, which is activated by inflammatory cytokines, and acts to reduce tryptophan availability to cysts. Both the immune and tryptophan/kynurenine effects could potentially cause low level parasitemia. Consistently lower levels of peripheral circulating inflammatory cytokines in the latently infected pregnant women suggest a global immunosuppression related to T.gondii and pregnancy induced T cell exhaustion. We are planning immunophenotyping and flow cytometry studies to determine if pregnancy associated TG latent infection produces T cell exhaustion.

Prescott, S., Mutka, T., Baumgartel, K., Yoo, J. Y., Morgan, H., Postolache, T. T., Seyfang, A., Gostner, J. M., Fuchs, D., Kim, K., & Groer, M. E. (2023). Tryptophan metabolism and immune alterations in pregnant Hispanic women with chronic Toxoplasma gondii infection. American journal of reproductive immunology 90(3), e13768.