Development of T cell memory

Immunological memory is defined as an antigen-induced altered state o f the immune system. There are an increased number o f antigen-specific T cells and qualitative differences in the expression o f cell surface molecules involved in adhesion and costimulation (Ahmed 1996). Cells in a memory population respond to previously encountered antigens with enhanced efficiency on re-exposure leading to a faster.

Chapter 1 : Introduction stronger and more prolonged response (Veiga-Femandes 2000). The use o f DNA microarrays showed that the expression of approximately 200 cDNA clones changed following T cell activation, these are expected to affect the different responses and properties of naïve, effector and memory CD4^ cells (Liu 2001). The enhanced response by memory cells is because the threshold o f detection is lower for memory than naïve cells, and that memory cells have a decreased dependency on CD28 mediated costimulation (London 2000, Fujii 1992).

The differentiation o f memory T cells is not clearly understood and is complicated by the many different methods of phenotypically defining different populations (discussed in section 1.7.2). Following naïve cell activation many o f the responding cells are susceptible to apoptosis by activation induced cell death (AICD), this prevents over expansion o f the T cell pool and is thought to be induced by granule mediated lysis (Opferman 2001, Opferman 1999, Callan 1998). However, previous studies have shown that AICD in CD4^ cells is Fas (CD95) dependent, whilst that in CD8^ cells is not (Algeciras 1998, Zimmerman 1996). The alternative regulation of AICD may explain quantitative differences in the detectable clone sizes o f CD4^ and CD8^ cells. It has recently been shown that CD4^ T cell help during the primary response is essential for secondary expansion and generation o f memory CD8^ cells, however it is not needed for the primary response (Janssen 2003).

The lineage relationship o f naïve, effector and memory cells is controversial. The conventional model of linear differentiation from naïve to effector to memory is supported by evidence that CD4^ T cell effectors can become memory cells without further division (Hu 2001). These data also agree with studies suggesting that there is

little differentiation of cells between effector and memory phases (Farber 1998). The transition from effector to memory CD4^ cells might be due to withdrawl of antigen stimulation (Harbertson 2002) suggesting that persistent antigen exposure is not required. Upon stimulation naïve CDS^ cells are committed to divide at least seven times and then differentiate into effector or memory cells (Kaech 2001). This is further supported by the observation that CDS^ cells acquire memory properties several weeks following viral clearance (Kaech 2002). Whilst these studies suggest a linear model of differentiation other studies have raised the possibility that memory cells can be derived directly from a subset o f naïve cells, bypassing the effector stage (Farber 1998). This alternative hypothesis is based on the observation that heat-stable antigen, which provides a weaker costimulatory signal than CD28, is able to drive naïve murine T cells to memory but not effector cells (Liu 1997).

The maintenance of immunological memory is another controversial area. There are many arguments for and against the role of antigen persistence in maintenance of memory. By definition ‘memory’ implies that cells do not continuously recognise antigen, however, most experimental models cannot exclude that some antigen is present and persistent antigen has been observed in some viral infections. Antigen can be maintained on follicular DCs as antigen-antibody complexes for long periods o f time (Beverley 1991). Long-lasting CTL responses to hepatitis B virus are related to trace amounts o f viral persistence detected by PGR (Rehermann 1996) and the RNA virus LCMV can generate cDNA transcripts and persist in mice (Klenerman 1997). In support o f the arguments for the requirement of antigen for maintenance o f memory there are impaired memory responses in B cell deficient mice (Gray 1996), and T cell memory declines with the removal of antigen (Kundig 1996). It was also found that CD4^

Chapter 1 : Introduction memory cells cannot migrate into peripheral lymph nodes in the absence o f antigen (Bradley 1999). However, more recent definition o f central and effector memory populations (discussed in Section 1.7.2) might account for these observations. In contrast transgenic systems have shown that CD4^ and CD8^ memory cells can be generated in an MHC independent manner, suggesting that antigen persistence is not essential (Swain 1999, Murali-Krishna 1999). Adoptive transfer experiments have also shown memory CD8^ cells to LCMV and influenza persist in the absence of antigen (Mullbacher 1994, Lau 1994). However, there are arguments that memory T cells by this definition do not necessarily correspond with protective immunity which is the true measure o f memory.

Homeostasis of memory populations is also dependent on cytokine exposure. Viruses and type I interferon (IFN) can initiate bystander proliferation o f CD8^ T cells in an antigen-independent manner (Tough 1996). It has been shown more recently that persistence and proliferation of naïve and memory cells have different cytokine requirements. In human CD4^ cells effector, but not central, memory cells expand well with IL-15 and IL-7 whereas naïve cells do not respond (Geginat 2001). Other studies have found that IL-7 is essential for the survival and proliferation o f naïve cells (Rathmell 2001, Tan 2001). In mice IL-15 and IL-7 regulate proliferation o f memory CD8^ but not CD4^ cells (Tan 2002). IL-15 has since been shown to promote the survival o f both naïve and memory CD8^ cells in mice (Berard 2003, Mueller 2003). The effects o f antigen and cytokines maintain homeostasis o f naïve and memory populations ensuring constant numbers o f T cells in the immune system.