Memory T cells

Immunological memory is the ability of immune system to respond more rapidly and effectively to previously encountered pathogens, reflecting the persistence of clonally expanded Ag specific lymphocytes as “memory T cells”. Most effector cells die at the end of immune response, and the differentiation of memory cells is still poorly understood.

A linear pathway of memory commitment was proposed in 1999, suggesting sequential differentiation of naive T cells to effectors and then to memory T cells (Opferman, J.T. et, al. 1999). In this theory, naive T cells become activated following Ag stimulation, differentiate into effectors and quickly expand to clear pathogens. After Ag clearance most effectors die, the cell numbers contract, and only a proportion of Ag experienced cells revert to a slowly cycling long-lived memory T cells. This is supported by lymphocytic choriomeningitis virus (LCMV) infection experiments showing that virus specific memory CD8 cells are derived from expanded effector cells (Murali-Krishna, K. et al 1998; Kaech, S.M. et al. 2001, 2002), and by adoptive transfer experiments showing that memory CD4 cells originate from Ag-activated effector T cells in vivo (Swain, S.L.1994; Garcia, S. et al. 1999).

However, accumulating evidence indicates the independence of memory T cell generation from effector differentiation. Lauvau G et al reported memory CD8+ T cell generation in vivo in the absence of an overt effector response (Lauvau, G. et al. 2001). Manjunath and colleagues showed that effector differentiation is not a

prerequisite for memory CD8+ cells (Manjunath, N. et al. 2001). Wu CY et al reported distinct effector cells have differential capacities for memory generation (Wu, C.Y. et al 2002). Farber’s group proved that memory T cells have functional plasticity in cytokine production (Ahmadzadeh, M. and Farber, D.L. 2002). They also showed that memory CD4 cells can be produced at different states of differentiation upon Ag stimulation from activated precursors, which have gradations of effector functions (Moulton, V.R. et al. 2006).

Figure 1.3.4 The intersecting pathway model of memory T cell formation

This model takes into consideration proliferative turnover, acquisition of effector function and cell survival in memory T cell generation driven from two pathways: antigen dependent activation and independent homeostasis. Naive T cells upregulate IL-2R and downregulate IL-7R receptor expression after Ag stimulation, resulting in rapid proliferation and differentiation to effectors, then contract to memory subset

after Ag clearance. Alternatively, naive T cells (CD25loIL-7Rhi) undergo slow

proliferative turnover in the expose of homeostatic factors like IL-7 and differentiate to memory-phenotype cells with effector capacity in the absence of specific antigen (Moulton, VR. & Farber, DL. 2006).

Memory-like T cells also arise without effector differentiation during homeostatic expansion in T cell depleted hosts to restore the circulating T cell pool. When naive T cells are adoptively transferred into lymphopaenic hosts, they acquire memory T cell phenotypes and functional properties during homeostatic proliferation, which is referred to as homeostasis driven memory T cell differentiation (Cho, B. et al. 2000; Goldrath, A.W. et al 2000; Murali-Krishna, K. and Ahmed, R. 2000).

Farber proposed a revised “intersecting pathway model” for memory T cell generation (Moulton, V.R. and Farber, D.L. 2006) (Figure 1.3.4). In this model, memory T cells can be generated through either Ag activation or Ag independent homeostatic factors. Naive T cells (CD25low IL-7Rhi) undergo rapid IL-2 driven proliferation by up-regulated CD25 (IL-2Rα chain) and down-regulation of CD127 (IL-7Rα chain), and differentiate into effectors when further exposed to Ag. In the absence of further Ag stimulation, activated T cells undergo slow proliferative turnover driving to memory phenotype cell differentiation by homeostatic factors especially by IL-7. The intersection of these two pathways occurs at Ag clearance due to down-regulation of IL-2Rα and up-regulation of IL-7Rα on intermediate “pre- memory” cells that can homeostatically differentiate into stable memory T cells.

Memory T cells have high heterogeneity. Sallusto firstly reported two subsets of T cells with distinct homing potentials and effector functions in human (Sallusto, F. et al. 1999). Central memory T cells (TCM) express CCR7 and CD62L that are required for

T cells to recirculate into the T cell area of secondary lymphoid organs. TCM do not

have immediate effector functions but they are sensitive to TCR stimulation and independent on costimulation. After priming, TCM produce IL-2 and then efficiently

differentiate into effector cells producing IFNγ or IL-4 (Sallusto, F. et al. 2004). Effector memory T cells (TEM) do not express CCR7 and only a proportion of TEM

express CD62L. Instead TEM express a set of chemokine receptors and adhesion

molecules required for homing to inflamed tissues. TEM have rapid effector functions

and produce large amount of perforin from CD8 TEM and IL-4, IFNγ, and IL-5 from

both CD4 and CD8 TEM (Williams, M.A. & Bevan, M.J. 2007). Even TCM and TEM

are heterogeneous in expression of costimulatory molecules, adhesion molecules, and chemokine receptors, which discriminate TCM and TEM into functional subsets in

resting status (Table 1.3).

Transcription factor T-bet has been linked with long-term renewal of memory CD8+ T cells and their responsiveness to IL-15 (Intlekofer, A.M. et al. 2005). It was recently revealed that the amount of inflammatory cytokines (i.e., IL-12) during T cell priming determines the fate of short-lived effector cells (SLECs) and memory precursor effector cells (MPECs) through a gradient expression of T-bet transcription factor, which potentially regulates memory commitment from activated CD8+ T cells (Joshi, N.S. et al. 2007).

In summary, memory T cells function as a dynamic repository of Ag experienced T lymphocytes that are generated from different precursors in multiple pathways. They are highly heterogeneous and mediate both protective and reactive immunity over the life time of the individual.

properties naïve effector memory

homogeneity/heterogeneity homogeneous heterogeneous heterogeneous

TH1, TH2, TH17, Treg TCM TEM

phenotype:

cell size small large small

adhesion molecules CD44lo CD44hi CD44hi CD44hi

CD11a (LFA-1)+ LFA-1 hi LFA-1 hi LFA-1 hi

CD62Lhi CD62Llo CD62Lhi CD62Llo

activation markers CD69lo CD69hi/lo CD69lo CD69lo

CD25- CD25+ CD25- CD25-

chemokine receptors CCR7hi CCR7lo CCR7hi CCR7lo

others CD45RA/RB/AC CD45RO CD45RO CD45RO

IL7Rhi IL7Rlo IL7Rhi IL-7Rhi

CD43lo CD43hi CD43hi CD43hi

Ly6c- Ly6C+ Ly6C+

effector functions mainly IL-2 IL-2, IFNr, TNF (TH1) effectors effectors

IL-4, IL-5, IL-10, IL-13 (TH2) IL-17, IL-22 (TH17) IL-10, TGFbeta (Treg) Cytotoxicity of CD8 cells

maximum cytokine secretion days hours (Rapid) days hours (rapid)

homing lymphoid tissues

lymphoid and non-lymphoid

tissues Lymphoid tissues non-lymphoid tissues

telomerase long long shorter shortest

half life weeks hours ~ days years Weeks-months

requirement of immune

response Ag at high concentration Ag at high concentration

Ag at low concentration

Ag at low concentration IL-10, TGFbeta (Treg)