Memory T cell


Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

Function

-specific memory T cells against viruses or other microbial molecules can be found in both TCM and TEM subsets. Although most information is currently based on observations in the cytotoxic T cells subset, similar populations appear to exist for both the helper T cells and the cytotoxic T cells. Primary function of memory cells is augmented immune response after reactivation of those cells by reintroduction of relevant pathogen into the body. It is important to note that this field is intensively studied and some information may not be available as of yet.
Clones of memory T cells expressing a specific T cell receptor can persist for decades in our body. Since memory T cells have shorter half-lives than naive T cells do, continuous replication and replacement of old cells is likely involved in the maintenance process. Currently, the mechanism behind memory T cell maintenance is not fully understood. Activation through T cell receptor may play a role. It is found that memory T cells can sometimes react to novel antigens, potentially caused by intrinsic diversity and breadth of the T cell receptor binding targets. These T cells could cross-react to environmental or resident antigens in our bodies and proliferated. These events would help maintain the memory T cell population. The cross-reactivity mechanism may be important for memory T cells at the mucosal tissues since these sites have higher antigen density. For those resident in blood, bone marrow, lymphoid tissues and spleen, homeostatic cytokines or major histocompatibility complex II signaling may be more important.

Lifetime overview

Memory T cells undergo different changes and play different roles in different life stages for humans. At birth and early childhood, T cells in the peripheral blood are mainly naive T cells. Through frequent antigen exposure, the population of memory T cells accumulates. This is the memory generation stage, which lasts from birth to about 20-25 years old, when our immune system encounter the greatest number of new antigen. During the memory homeostasis stage that comes next, the number of memory T cells plateaus and is stabilized by homeostatic maintenance. At this stage, the immune response shifts more towards maintaining homeostasis since few new antigens are encountered. Tumor surveillance also becomes important at this stage. At later stages of life, at about 65-70 years of age, immunosenescence stage comes, in which stage immune dysregulation, decline in T cell functionality and increased susceptibility to pathogens are observed.

Lineage debate

As of April 2020, the lineage relationship between effector and memory T cells is unclear. Two competing models exist. One is called the On-Off-On model. When naive T cells are activated by T cell receptor binding to antigen and its downstream signaling pathway, they actively proliferate and form a large clone of effector cells. Effector cells undergo active cytokine secretion and other effector activities. After antigen clearance, some of these effector cells form memory T cells, either in a randomly determined manner or are selected based on their superior specificity. These cells would reverse from the active effector role to a state more similar to naive T cells and would be "turned on" again upon the next antigen exposure. This model predicts that effector T cells can transit into memory T cells and survive, retaining the ability to proliferate. It also predicts that certain gene expression profile would follow the on-off-on pattern during naive, effector and memory stages. Evidence supporting this model includes the finding of genes related to survival and homing that follow the on-off-on expression pattern, including interleukin-7 receptor alpha, Bcl-2, CD26L and others.
The other model is the developmental differentiation model. This model argues that effector cells produced by the highly activated naive T cells would all undergo apoptosis after antigen clearance. Memory T cells are instead produced by naive T cells that are activated, but never entered with full-strength into the effector stage. The progeny of memory T cells are not fully activated because they are not as specific to the antigen as the expanding effector T cells. Studies looking at cell division history found that the length of telomere and activity of telomerase were reduced in effector T cells comparing to memory T cells, which suggests that memory T cells did not undergo as much cell division as effector T cells, which is inconsistent with the On-Off-On model. Repeated or chronic antigenic stimulation of T cells, like HIV infection, would induce elevated effector functions but reduce memory. It was also found that massively proliferated T cells are more likely to generate short-lived effector cells, while minimally proliferated T cells would form more long-lived cells.

Epigenetic modifications

modifications are involved in the change from naive T-cells. For example, in CD4+ memory T cells, positive histone modifications mark key cytokine genes that are up-regulated during secondary immune response, including IFNG, IL4, and IL17A. Some of these modifications persisted after antigen clearance, establishing an epigenetic memory that allows a faster activation upon re-encounter with the antigen. For CD8+ memory T cells, certain effector genes, such as IFNG, would not be expressed but they are transcriptionally-poised for fast expression upon activation. Additionally, the enhancement of expression for certain genes also depends on the strength of the initial TCR signaling for the progeny of memory T cells, which is correlated to the regulatory element activation that directly changes gene expression level.

Sub-populations

Historically, memory T cells were thought to belong to either the effector or central memory subtypes, each with their own distinguishing set of cell surface markers. Subsequently, numerous additional populations of memory T cells were discovered including tissue-resident memory T cells, stem memory TSCM cells, and virtual memory T cells. The single unifying theme for all memory T cell subtypes is that they are long-lived and can quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen. By this mechanism they provide the immune system with "memory" against previously encountered pathogens. Memory T cells may be either CD4+ or CD8+ and usually express CD45RO and at the same time lack CD45RA.

Memory T cell subtypes

There have been numerous other subpopulations of memory T cells suggested. Investigators have studied Stem memory TSCM cells. Like naive T cells, TSCM cells are CD45RO−, CCR7+, CD45RA+, CD62L+, CD27+, CD28+ and IL-7Rα+, but they also express large amounts of CD95, IL-2Rβ, CXCR3, and LFA-1, and show numerous functional attributes distinctive of memory cells.