Phenotypic Differentiation of T Cells During Ageing

There are numerous ways in which human T cell differentiation can be characterised [15,16], the most common being listed in Table 2.1. However the most striking characteristic of highly differentiated T cells is the loss of the co-stimulatory molecules CD27 and CD28 and the re-expression of CD45RA, with CD8+ T cells losing CD28 first followed by CD27 with the inverse being true for CD4+ T cells [15, 17, 18]. Initially, it was thought that the loss of CD28 was the predominant factor controlling reduced activity in these cells [19]. However, highly differentiated T cells show considerable redundancy in co-stimulatory receptor usage, and alternative receptors, such as OX40 and 4-1BB can promote T cell activation in CD28-CD8+ populations [8, 20]. Highly differentiated T cells also increase during ageing with similar phenotypic changes occurring in both CD4+ and CD8+ T cells. However the rate at which these changes happen varies within each subset, with age-related changes being more pronounced on CD8+ T cells, possibly due them exhibiting a greater homeostatic stability than CD4+ T cells [21].

Highly differentiated T cells remain functional and secrete high levels of cytokines such as interferon-y (IFNy) and tumour necrosis factor (TNFa), together with high

Table 2.1 Phenotypic and functional characteristics of differentiated human T cells

Early differentiated

Mid differentiated

Late differentiated

Differentiation

CD45RA

+++

CD45RA

+/-

CD45RA

-/+

CD27

+++

CD27

+

CD27

-

CD28

+++

CD28

+/-

CD28

-

CCR7

+++

CCR7

+++

CCR7

-

CD62L

+++

CD62L

+++

CD62L

-

CD57

+

CD57

++

CD57

+++

Cytotoxicity

+

Cytotoxicity

++

Cytotoxicity

+++

Proliferation

++

Proliferation

++

Proliferation

+/-

Senescence

KLRG1

+

KLRG1

++

KLRG1

+++

Bcl-2

+++

Bcl-2

++

Bcl-2

+

Telomere

+++

Telomere

++

Telomere

+

Telomerase

+++

Telomerase

++

Telomerase

-

P-Akt

+++

P-Akt

++

P-Akt

-

P-mTORC1

++

P-mTORC1

+++

P-mTORC1

-

ROS

+

ROS

++

ROS

+++

levels of granzyme B and perforin expression, indicating that they have the potential to mediate high cytotoxic activity [16, 22-25]. Furthermore, highly differentiated CD27-CD28- T cells remain polyfunctional secreting interleukin-2 (IL-2), IFNy and TNFa, and expressing CD40 ligand, to the same extent as less differentiated memory T cell populations [22, 26, 27]. However, these cells have reduced capacity to replicate after activation [17,27] and are susceptible to apoptosis ex vivo but it is possible that CD27-CD28- T cells may persist in vivo in the presence of appropriate survival signals [28]. Taken together this suggests that highly differentiated T cell populations have characteristics of short-lived effector T cells, namely, potent effector function and susceptibility to apoptosis [29].

In addition, highly differentiated T cells become less reliant on specific antigen for stimulation and more prone to activation through innate receptors. Including killer immunoglobulin-like receptors (KIRs), killer cell lectin-like receptors (KLRs), and the immunoglobulin-like transcript receptors (ILT/CD85), more typically associated with NK cell function [30]. The acquisition of these receptors on highly differentiated T cells is more frequently seen on CD8+ than CD4+ T cells [31]. The majority of these NK receptors recognise MHC class I molecules [32], thereby circumventing the need for antigen recognition, which restricts clonal expansion and offers protection from undue repertoire skewing. Interestingly, NK receptors are not the only innate molecules to increase on end-stage T cells, recent evidence suggests that Toll-like receptor (TLRs) are also upregulated. TLRs appear to be more important for CD4+ T cell function, displaying higher levels of TLR2/4 expression than CD8+ T cells [33]. However the pattern recognition molecule retinoic acid inducible gene I (RIG-I)-like helicase was found to be more important for highly differentiated CD8+ T cell function [33]. This suggests that differential expression of TLRs and RIG-1 on CD4+ and CD8+ T cells may reflect distinct modes of antigen-independent T cell priming.

 
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