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.
Primary
Sources:
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.
Other Sources:
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