The adaptive immune system is composed of several cell types that seek and destroy invading pathogens. One of these cell types is T cells that bind to epitopes, or unique protein fragments, to see if these molecules come from invading pathogens. T cell populations include both naïve and memory T cells that expand and contract in abundance and compete for resources and epitope binding sites as they sample the surrounding area. While the competition between T cell populations has been observed, the process of how this struggle resolves during virus infection is not well understood. A multi-division collaboration between the Labs of Drs. Michael Boeckh, Phil Bradley, and Martin Prlic was formed to investigate the coordination of naïve and memory T cells in response to viral infection by cytomegalovirus (CMV). Their findings were published recently in PNAS.
This project originated when a unique set of patient samples became available. “Michael [Boeckh] had samples from this very unique patient cohort described in the paper that let us concurrently study a naïve (donor-derived) and memory (patient-derived) T cell response to CMV (with defined CMV reactivation events),” Dr. Prlic explains. This unique cohort of individuals was seropositive for CMV, meaning they were infected with a dormant or non-replicating herpesvirus, and also required stem cell transplantation. The specific type of stem cell transplantation used for these individuals only moderately reduced the patient’s immune response, which allowed the researchers to follow the patient’s memory T cell response to CMV, a virus that reactivates during patient immune suppression. The donor T cells represent a naïve population that has not “seen” CMV-specific epitopes. In this study, donor cells were distinguished from the transplant recipient cells by male versus female-specific genes for the sex mis-matched donor-recipient transplants. For sex-matched cases, the researchers used single nucleotide polymorphisms that differentiated the donor and recipient cell populations. Consequently, the blood samples taken from these patients following stem cell transplantation enabled the researchers to study the T cell response to CMV infection for the memory (patient-derived) and naïve (donor-derived) T cell populations.
The researchers first characterized the expansion of T cell populations following transplantation. As might be expected, the donor-derived T cells expanded extensively following transplantation while the patient-derived T cells exhibited only modest expansion. With these T cell population dynamics in mind, the researchers moved to characterize T cell expansion for cells that specifically recognize CMV epitopes. Dr. Prlic emphasized that, “Phil Bradley’s expertise in analyzing [T cell receptor] TCR sequence data was critical to find these congruent [CMV-specific] T cell clones” from the naïve donor-derived and memory patient-derived cell populations. Although the donor T cells represented the majority of all T cells, the patient-derived memory T cells specific to CMV were more abundant than the donor cells specific to CMV epitopes (figure).
Investigating this CMV-specific population more closely revealed that the TCR sequences between this subset of donor and recipient T cells had extremely high sequence similarity. Referencing these findings, Dr. Bradley commented, “I was really struck by the convergent selection of such similar TCR clonotypes within this narrow window of time.” These data suggested that select naïve donor T cells add to the memory T cell specific response to CMV infection. Therefore, while different populations of T cells expand and contract during virus infection, naïve cells with near-matching TCR to expanding memory T cells can converge to increase the effect of the adaptive immune response on an invading pathogen. This synchronized response to infection highlights the efficiency and complexity of our adaptive immune system and provides insight into the toggle between T cell competition and synergy.
These findings contributed to the field’s general understanding of T cell expansion and targeted response following CMV replication and the dynamics of naïve and memory T cell populations. Dr. Prlic adds, “From a basic immunology point-of-view it is just amazing and really cool to find CMV-specific T cells with identical TCRs (incl CDR3 on the amino acid level) that are donor and recipient-derived. This highlights that there is competition between T cells to respond to antigen and that the selection process for these responding, antigen-specific T cells is quite stable and reproducible.”
The spotlighted research was funded by the National Institutes of Health. First author Jami Erickson was an Eddie Mendez Scholar while conducting this published research.
UW/Fred Hutch Cancer Consortium members Michael Boeckh, Philip Bradley, and Martin Prlic contributed to this work.
Erickson JR, Stevens-Ayers T, Mair F, Edmison B, Boeckh M, Bradley P, Prlic M. 2022. Convergent clonal selection of donor- and recipient-derived CMV-specific T cells in hematopoietic stem cell transplant patients. Proc Natl Acad Sci USA. 119(6):e2117031119.