Clinical Information

T cells, after completing development and initial differentiation in the thymus, enter the periphery as naive T cells. Naive T cells undergo further differentiation into effector and memory T cells in the peripheral lymphoid organs after recognizing specific antigenic peptides in the context of major histocompatibility (MHC) molecules, through the antigen-specific T-cell receptor. In addition to the cognate signal of the peptide-MHC complex interaction (the term cognate refers to 2 biological molecules that normally interact), T cells require additional costimulatory signals to complete T-cell activation. Naive T cells circulate continuously through the lymph nodes and, on recognition of specific antigen, undergo activation. Due to their antigen-inexperienced state, naive T cells require activation by more potent antigen-presenting cells, such as dendritic cells.

Naive T cells can survive in circulation for prolonged periods of time and are very important in contributing to T-cell repertoire diversity. They proliferate in response to interleukin-2 as a consequence of their response to antigen through recognition of peptide-MHC costimulation. These expanded antigen-specific T cells undergo further differentiation into effector cells. The differentiation of naive CD8 T cells into cytotoxic effectors capable of killing target T cells loaded with endogenous peptides on MHC class I molecules may require additional costimulatory signals from CD4 T cells. Naive CD4 T cells also differentiate into different effector subsets such as Th1, Th2, and Th17, which produce specific cytokines.(1)

T cells can be subdivided into naive and memory subsets based on the expression of cell-surface markers, such as CD45RA and CD45RO among others. It was initially thought that the presence of cell-surface CD45RA indicated the naive subset, while the presence of CD45RO indicated memory subsets. It has now been shown that multiple, rather than single, markers are required to distinguish these subsets.(2) Lanzavecchia and Sallusto proposed a model where naive T cells expressing CD45RA and CCR7 lose CD45RA expression on recognition of antigen.(3) The surface markers for identifying naive T-cell subsets include CD45RA, CD62L (L-selectin), and CD27.(4,5)

Memory T cells are antigen-experienced cells that are present in greater numbers than antigen-specific precursors and can respond more efficiently and rapidly to a specific antigen. Memory T cells can maintain their populations independent of antigen by homeostatic proliferation in response to cytokines. While there are subcategories of memory T cells based on effector function and cell surface and cytolytic molecule expression, the 2 main categories of memory T cells are central memory T cells (Tcm) and effector memory T cells (Tem).(1,6)

Tcm express the CD45RO molecule along with CD62L (L-selectin) and CCR7 and are present mainly in lymphoid tissue.(6,7) They can respond to antigens through rapid proliferation and expansion and differentiation into Tem. By themselves, Tcm are not directly effective in effector cytolytic function.

Unlike Tcm, Tem express only CD45RO (not CD62L and CCR7).(6) As the name suggests, Tem have remarkable effector function, though they do not proliferate well. Tem are present throughout the circulation in peripheral tissues providing immune surveillance.

Memory T cells are particularly important for maintenance of immune competence since they are associated with a rapid and effective response to pathogens. Therefore, depletion of this compartment has more immediate significance than the depletion of naive T cells.

Activation of human T cells is critical for the optimal and appropriate performance of T-cell functions within the adaptive immune response. Activated naive T cells undergo proliferation, as well as subsequent differentiation into effector T cells, and are capable of producing cytokines that can modulate the immune response in a variety of ways.(8) There are several markers associated with T-cell activation, but those most commonly used include CD25 (IL-25R)(8) and MHC class II.(9) Additionally, the expression of the costimulatory molecule CD28 augments the T-cell activation response.(10)

The absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors, including hormones, the environment, and temperature. The studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T-cell count throughout the day, while CD8 T cells and CD19+ B cells increase between 8:30 a.m. and noon, with no change between noon and afternoon. Natural killer cell counts, on the other hand, are constant throughout the day.(11) Circadian variations in circulating T-cell counts have been shown to be negatively correlated with plasma cortisol concentration.(12-14) In fact, cortisol and catecholamine concentrations control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T cells.(11) It is generally accepted that lower CD4 T-cell counts are seen in the morning compared with the evening,(15) and during summer compared to winter.(16) These data therefore indicate that timing and consistency in the timing of blood collection are critical when serially monitoring patients for lymphocyte subsets.