CD4+ T cells, also known as helper T cells (Th cells), support B and T cell immune responses (more on helper T cells). Once activated, Th cells differentiate into different effectors, depending on chemical factors in the local environment, called cytokines. One of these effectors is Th1, mainly involved in an antiviral response or response combating intracellular pathogens. After the antigen has been cleared from the system, most of the Th1 cells are eliminated by immune system controls, however, a small number of the Th1 cells survive and differentiate into memory T cells. Although the process in which Th cells differentiate into Th1 cells has been extensively studied, very little is known about the differentiation of Th1 cells into memory cells! Knowing the steps involved in memory cell differentiation is important, because not only do they indicate the factors that effect T cell fate, but this knowledge could be used to design better vaccines that are aimed at increasing memory T cell formation! T cell receptors (TCRs) (more on T cells and TCRs) create signals during activation that impact the differentiation and expansion of the T cell, therefore, there is a possibility that TCR signaling determines the end fate of T cells as well: whether they become long-lived memory T cells or end-stage effectors to be eliminated after the pathogen has been cleared.
In a recent study, Kim et al investigated the impact of TCR signals on the end fate of Th1 cells. They determined which TCR-binding characteristics correspond to memory differentiation. To do this, they cloned TCR sequences obtained in a deep sequencing process, and then they transfected 293 T cells with TCR retroviral expression vectors so they could express these TCRs. Next, the T cells were infected with GP 66-77 tetramer (an antigen glycoprotein), and the tetramer off rates (the rate at which TCR and pMHC dissociate) and avidity (number of TCR-pMHC interactions occurring) for TCRs were measured. Some TCRs had high avidity with quick off rates, and some had low avidity with extremely slow off rates. When compared to TCR survival 8-42 days after infection, the only significant predictor of memory T cell potential was the tetramer off rate.
Next, four TCR clones were selected that exhibited a wide range of tetramer off rates and binding avidities. The memory potential of each effector Th1 cell population, measured as the decline in T cell numbers 8-42 days after infection, varied widely. The memory potential of each clone corresponded to tetramer off rates.
Overall, the study concluded that stable and sustained TCR-pMHCII interactions are a key component of the memory T cell differentiation signal for Th cells.
This study is interesting in that it investigates a differentiation process that has not been studied- because although the differentiation of Th cells into Th1 and Th2 effectors has been thoroughly looked at, the factors that decide the end fate of Th cells has been unknown. Future studies will have to focus on the ways in which T cell intrinsic and extrinsic factors cooperate to initiate memory cell differentiation, as this piece of the puzzle still remains unknown. I think that the results of this study and future studies related to this will be important in the creation of new medicines and vaccines that rely on rapid immune responses of memory cells.
Kim C, T Wilson, KF Fischer, and MA Williams. 2013. Sustained Interactions between T Cell Receptors and Antigens Promote the Differentiation of CD4+ Memory T Cells. Immunity, 39: 508-520.