In contrast to naive T cells, Memory/effector cells migrate mostly through peripheral tissues. This migration mediates rapid protective responses and is controlled by the expression of different sets of integrins and chemokine receptors. However, some memory T cell must also reach the lymph nodes to mount secondary proliferative responses.

Memory T cells are more responsive than naive T cells. A lower Ag dose as well as lower co-stimulatory requirements is required for stimulation. TMEMS display faster and strong display of effector function.

CD4+ T cells of memory phenotype hone to nonlymphoid tissues such as liver, lung, intestine or skin rather than to LN. In human, memory T cells have originally been described as expressing CD45RO isoform rather then the CD45RA isoform of naive T cells. Recently, however, several studies have suggested that memory T cells specific for some viral antigens could express the CD45RA isoform instead.

Tmem refers to antigen experiened T cells that express the phenotypic markers TCRalpha, TCRbeta, CD3, CD4 or CD8, CD95 and IL-2Rbeta. (US 10,300,090)

T memory Cell subsets

Immunological memory is displayed by two distinct T cell subsets; lymph-node homing cells lacking inflmmatory and cytotoxic function (TCM) and tissue homing cells endowed with various effector function (TEM). These two subsets allow a division of labor among memory cells. On the one hand, TEM cells represent a readily available pool of antigen primed cells which can enter peripheral tissues to mediate inflammatory reaction or cytotoxicity, thus rapidly containing invasive pathogens. On the other hand, TCM cells represent a clonally expanded antigen primed population which travels to secondary lymph organs and upon a secondary challenge, can efficiently stimulate DC, help B cells and generate a new wave of effector cells.

Both central and effector subsets express disturbed T cell repertoires.

Central memory T (TCM) cells: TCM cells express CC-chemokine receptor 7 (CCR7) and CD62L, and are found in lymphoid organs. CCR7+ memory cells express intermediate levels of ?1 ?2 integrins, as well as CCR4, CCR6 and CXCR3 on various proportions of cells. 

Functionally, CCR7+ memory T cells are distinguished by their failure to secrete cytokines in response to brief antigenic stimulation. CCR7+ memory cells produce IL-2 only like naive T cells.

T central memory cells refers to an antigen experienced T cell that expresses the phenotypic markers CD4 or CD8, CD62L, CD45RO, CCR7, IL-2Rbeta, CD28, CD127 and CD95 and does not express or has low expression of CD45RA as compared to native T cells. Central membory T cells can differentiate into TEM cells following antigen re-challenge. (US 10,300,090)

Effector memory T (TEM) cells: TEM cells cells do not express either CCR7 or CD62L, and they reside in non-lymphoid tissues and mediate effector functions immediately after activation. CCR7- memory cells express high levels of ?1 ?2 integrins which are required for homing to inflamed tissues as well as tissue specfiic homing receptors such as CD103 and CLA. Receptors for inflammatory chemokines such as CCR1, CCR3 and CCR5 are selectively expressed.

CCR7- memory cells rpoduce high levels of IL-4, IL-5 and IFNy and moderately reduced levels of IL-2. CCR7- memory have perforin contianing granules. CD8+CCR7- memory T cells have been named effector cells because they express perforin and are cytotoxic ex vivo, whereas CCF7+ memor T cells need a short-term restimulation to acquire these functions.

T effector memory cells refers to an antigen experienced T cell that expresses the phenotypic markers CD4 or CD8, CD45RO, CD127, IL-2Rbeta and CD95 and does not express or has low expression of CD45RA, CD62L, CCR7 and CD28. T effector memory cells are terminally differentiated and acquire effector function after restimulation by antigen. (US 10,300,090)

T stem central memory cells: refers to an antigen experienced T cell that express the phenotypic markers CD4 or CD8, CD45RA, CD62L, CD95, IL-2Rbeta, CCR7, CXCR3, CD122 and LFA-1. TSCM cells possess memory T cell capability of rapid acquisition of effector function following antigen re-challenge, but have enhanced stem cell-like qualities such as long-term persistence compared to TCM cells. TSCM cells can generate central memory, efffector memory and effector T cell subsets (US 10,300,090). 

T memory Cell Differentiation

In response to an invading pathogen, T cells specific for foreign antigen expand exponentially and differentiate into effector cells that clear the infection. At the end of the immune response, most of the expanded T cell die with a small portion of the survivors remaining as memory T cells. There are three phases of memory generation;

(1) expansion phase which takes days. Memory T cells arise from effector cells. See T cell activation Various factors are involved in T cell activation including Ag density, duration of stimulation, activation of innate immune (upregulation of co-stimulatory molecules). This is important for TMEM generation because weak stimulation may lead to an abortive response and tolerance.

(2) contraction/selection phase which takes weeks. In this phase death of 90% of effector cells and selection of memory cells. IL-7R appears to mark memory precursors.

Down-regulation of T-cell proliferation occurs by an apoptotic program that is initiated after activation. After T-cell activation, c-FLIP expression is reduced, and the cells become susceptible to Fas ligation and to caspase 8-mediated apoptosis. Exposure to a second activation stimulus (eg, CD3 stimulation in the absence of CD28 costimulation) promotes de novo production of Fasl, leading to both autocrine and paracrineFas/FasL-mediated T-cell apoptosis.

Two pathways lead to apoptosis in T cells. In the first, activated peripheral T cells are induced to express high levels of Fas and FasL leading eventually to the cleavage of procaspase 8 to form active caspase 8. Second, other signals like the engagement of the TCR by peptide-MHC complexes on an APC result in the activation of the mitochondrial death pathway resulting in the release of cytochrome c from the inner mitcohondrial membrane into the cytosol.

T cells can be induced to die by many different signals, including the withdrawal of growth factor, treatment with glucocorticoids, or TCR signaling. Each of these signals engages unique signaling pathways but all involve the activation of a specialized set of proteases called caspases.

(3) maintenance phase which occurs for years. In this phase, long term survival of memory cells poised to respond to the same Ag in a faster and stronger manner.

Functions of Memory CD8 T cells

Virus-specific memory cells that persist in the absence of antigen following resolution fo an acute infection are maintained as fully functional populations capable of immediate synthesis of IFN?, TNF? and IL-2 upon reencountering an antigen. As effectors during acute infection, these Cd8 T cells are highly cytolytic. As memory T cells they can secrete cytokines, beigin to prolfierate and become cytolytic effectos more rapidly than niave cells upon reexposure to antigen.

Interestingly, when virus persists, CD8 T cells with abnormal function may arise.