Memory T cells in organ transplantation: progress and challenges

Abstract

Antigen-experienced T cells, also known as memory T cells, are functionally and phenotypically distinct from naive T cells. Their enhanced expression of adhesion molecules and reduced requirement for co-stimulation enables them to mount potent and rapid recall responses to subsequent antigen encounters. Memory T cells generated in response to prior antigen exposures can cross-react with other nonidentical, but similar, antigens. This heterologous cross-reactivity not only enhances protective immune responses, but also engenders de novo alloimmunity. This latter characteristic is increasingly recognized as a potential barrier to allograft acceptance that is worthy of immunotherapeutic intervention, and several approaches have been investigated. Calcineurin inhibition effectively controls memory T-cell responses to allografts, but this benefit comes at the expense of increased infectious morbidity. Lymphocyte depletion eliminates allospecific T cells but spares memory T cells to some extent, such that patients do not completely lose protective immunity. Co-stimulation blockade is associated with reduced adverse-effect profiles and improved graft function relative to calcineurin inhibition, but lacks efficacy in controlling memory T-cell responses. Targeting the adhesion molecules that are upregulated on memory T cells might offer additional means to control co-stimulation-blockade-resistant memory T-cell responses.

Figure 1. Plasticity of memory T cells

a | Sequential differentiation of T cells as a linear model of progression from naive to effector, then effector memory and central memory. b | Parallel differentiation occurs when an activated T cell divides to yield two distinct daughter cells with either effector or memory capabilities. c | Combined pathway of T-cell development and memory formation integrating models of parallel and sequential differentiation.

Figure 2. Immunosuppressive agents target molecules that are differentially expressed on naive and memory T cells

a | Naive T cells express high levels of CD28 and are susceptible to inhibition by belatacept. b | Memory T cells express low levels of co-stimulatory molecules but upregulate the co-inhibitory molecule CD2 and adhesion molecules such as leukocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4). These molecules can also be specifically targeted: CD2 is inhibited by alefacept, LFA-1 is inhibited by efalizumab, and VLA-4 is inhibited by natalizumab. Both naive and memory T cells are susceptible to depletion using rabbit antithymocyte globulin (rATG) or alemtuzumab, which targets CD52. Calcineurin inhibitors (for example, tacrolimus) and mTOR inhibitors (for example, sirolimus) inhibit downstream cell signalling in naive and memory T cells during T-cell activation and thus prevent T-cell responses. FKBP, FK506-binding protein; TCR, T-cell receptor.