Circulating and resident memory T cell functions in viral diseases

A typical viral infection begins with the activation of the innate immune response, which recognizes viral components and initiates early defense mechanisms. This, in turn, enhances antigen presentation and stimulates the adaptive immune response, ultimately leading to infection resolution and the establishment of immunological memory. Memory T cells are central to long-term immunity and can be broadly classified into circulating and tissue-resident memory T cells (TRM), each playing distinct roles in immune surveillance. The coordination of immunity between these memory subsets is critical for effective control of both acute and chronic infections.

This thesis explores the dynamics of circulating and tissue-resident memory T cell responses against viral infections, with the goal of increasing our understanding of effective human immunity and advancing vaccine development and immunotherapeutic strategies.

In Study I, we investigate the antiviral and immunosurveillance function of CXCR5+ mCD8+ T cells in human blood and tonsil tissue, with a specific focus on Epstein- Barr virus (EBV) infection. We identified CXCR5 as a marker for CD8+ T cell tissue residency in human tonsil and observed that CD8+ T cells targeting antigens from the latent phase of the infection are predominantly localized in tonsil, the primary site of EBV reservoir.

In Study II, we present a comprehensive analysis of the HIV immune response and HIV reservoir in the blood and gastrointestinal (GI) tract of people living with HIV (PLWH). Our findings indicate that CCR5+ CD4+ T cells exhibiting a TRM phenotype are depleted in the GI tract of HIV-infected individuals. Furthermore, we observe a larger HIV reservoir in the GI tract compared to blood, and note a tendency for its contraction in the presence of HIV-specific memory CD8+ T cells.

In Study III and IV, we present the development of robust adaptive immunity against SARS-CoV-2 post-infection, and the effects of COVID-19 vaccination on the immune response to SARS-CoV-2 infection.

List of scientific papers

I. Rivera-Ballesteros, O., Cai, C., Sekine, T., Nilsén, V., Adamo, S., R. Müller, T., Constanz, C., Kammann, T., Mouchtaridi, E., Gao, Y., Akhirunnesa, M., J. M. Raineri, E., Stamper, C., Marchalot, A., Wild, N., Brownlie, D., Llewellyn-Lacey, S., Tibbitt, C., Michaëlsson, J., Marquardt, N., Mjösberg, J., Jorns, C., K. Sandberg, J., Driving, J., A. Price, D., & Buggert, M. CXCR5+ CD8+ T cells in tonsils mark a tissue- resident subset with elevated specificity for latent EBV antigens. [Manuscript]

II. Rivera-Ballesteros, O., Kieri, O., Cai, C., Birk, M., Hedström, A., Nowak, P., & Buggert, M. Resident and circulating T cell characteristics and viral reservoir dynamics across the gastrointestinal tract in diverse people living with HIV. [Manuscript]

III. Sekine, T *. , Perez-Potti, A *. , Rivera-Ballesteros, O *. , Strålin, K., Gorin, J .- B., Olsson, A., Llewellyn-Lacey, S., Kamal, H., Bogdanovic, G., Muschiol, S., Wullimann, D. J., Kammann, T., Emgård, J., Parrot, T., Folkesson, E., Akber, M., Berglin, L., Bergsten, H., Brighenti, S., . . . Buggert, M. (2020). Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19. Cell, 183(1), 158- 168.e114.
https://doi.org/https://doi.org/10.1016/j.cell.2020.08.017

IV. Cai, C., Gao, Y., Adamo, S., Rivera-Ballesteros, O., Hansson, L., Österborg, A., Bergman, P., Sandberg, J. K., Ljunggren, H. G., Björkström, N. K., Strålin, K., Llewellyn-Lacey, S., Price, D. A., Qin, C., Grifoni, A., Weiskopf, D., Wherry, E. J., Sette, A., Aleman, S., & Buggert, M. (2023). SARS-CoV-2 vaccination enhances the effector qualities of spike-specific T cells induced by COVID-19. Sci Immunol, 8(90), eadh0687.
https://doi.org/10.1126/sciimmunol.adh0687

*These authors contributed equally to this work.