T Cells

Similar to B cell development, T cell development undergoes several stages and can be followed by the combined expression of specific cell-surface receptors. Certain cell-surface markers have different expression patterns in humans and mice. For example, Thy-1, an Ig-like glycoprotein, is present on both thymocytes and peripheral T cells in mice but only on rat thymocytes (Tokugawa et al., 1997). In humans, Thy-1 expression is found only on stem cells and disappears from thymic progenitors. Thus, Thy-1 is used as a stem cell marker in humans, but as a T-cell marker in mice (Spits et al., 1998). With the exception of some species-specific cell-surface receptors (CD44 and CD25) to indicate T cell differentiation stages in the mouse, the major features of T cell development are similar in humans and mice. One striking difference between human and mouse T-cells is the expression of the CD8« and CD8^ isoforms (Spits et al., 1998). These CD8 receptor isoforms can appear as homodimers or heterodimers on T cells. Furthermore, interaction with the CD8 receptor and MHC I on thymic cortical epithelial cells is important for T cell development in the thymus. The double positive (DP) (i.e., expressing both CD4 and CD8 receptors) T cells in the thymus are positively selected based on functionality of CD4 and/or CD8. In mice, 60% of CD8« is normal, being able to bind to p56LCK, whereas the other 40% is an isoform (CD8«') resulting from alternative splicing. CD8«' has a short cytoplasmic domain preventing interaction with p56LCK (Zamoyska and Parnes, 1988). This truncated CD8a' isoform is not generated in humans or rats; thus, the balance of CD4+ and CD8+ mature T cell populations in the periphery may be different between humans, rats, and mice (Barber et al., 1989; Zamoyska and Parnes, 1988). The integrated work of other genes that activate specific transcription factors at different stages is essential to T cell development. Zap-70, a protein tyrosine kinase (PTK), is critical in signaling pathways initiated by T cell receptor (TCR) engagement. In Zap-70 knockout mice, T cell differentiation is stopped at CD4+ CD8+ DP stage; in humans, Zap-70 defects lead to SCID. Patients with SCID express CD4+ T cells with defective function. These studies indicate that Zap-70 is a key element for both CD8+ and CD4+ T cell development in mice but is required only for CD8+ T cell development in humans. This difference in humans may be due to the PTK, Syk, which can partially compensate for Zap-70 function in human T cell development. Syk expression is higher in human T cells when compared to mouse T cells (Chu et al., 1999; Elder et al., 2001).

Optimal activation of mature T cells requires two signals. The first (mandatory) signal involves stimulation of the Ag-specific TCR/CD3 complex. The second costimulatory signal is derived from various other receptors on the T cell. To date, the CD28 receptor is the best studied costimulatory signal. The CD28 receptor on T cells is activated by interacting with B7-1 receptors on antigen presenting cells, and there are several differences in the B7-CD28 family's expression and function in humans and mice. First, CD28 is expressed on almost all mouse CD4+ and CD8+ T cells, but only 80% on human CD4+ and 50% on human CD8+ T cells (Lenschow et al., 1996). Second, ICOS deficiency in mice causes deficient B cell reactivity and Ig isotype switching, which can be reversed by CD40 stimulation (Wang and Chen, 2004). In humans, the ICOS mutation alters B cell development resulting in decreased B cell numbers and no memory B cells (Wang and Chen, 2004). Since ICOS has proven to be required for proper T helper cell function (Wang and Chen, 2004), ICOS may have different effects on T helper cell function to regulate B cell differentiation, Ig isotype switching, and generation of memory B cells. The biggest difference of the B7-CD28 family between humans and mice exists in the function of the B7-H3 receptor. In humans, it functions to enhance the T cell response, but in mice, it inhibits T cell activation and subsequent cytokine generation (Prasad et al., 2004). Since the members of the B7-CD28 family have multiple functional consequences on T cell function, homeostatic T cell function can be maintained by altering the expression levels of these receptors in response to various stresses and stimuli.

Another interesting difference between human and mouse T cells is the expression of MHC-II. Normally, MHC-II molecules are expressed on professional Ag presenting cells (APCs) and function to present Ag peptide to CD4+ T helper cells initiating an Ag-specific immune response. MHC-II is also expressed on human T cells following T cell activation and its synthesis is regulated by the class II transactivator (CIITA) using the CIITA promotro III (CIITA-PIII). In contrast, MHC-II receptors are not found on activated mouse T cells most likely because CIITA-PIII is methylated, preventing CIITA transcription (Holling et al., 2004). It is currently thought that MHC-II bearing T cells can work like APCs to process and present exogenous Ag to other T cells. It is not clear whether the antigen presenting function of human T cells results in increased T cell activation, clonal anergy, or apoptosis (Holling et al., 2004).

Once the TCR is engaged, TCRf and CD3 chains are phosphorylated immediately, which consequently activates the Src and Syk PTK family kinases and a cascade of adaptor and effector proteins, ultimately resulting in cytokine production and cell proliferation. One of the key pathways involved in human T cell activation is the PKC-dependent activation of the phosphatidylinositol (PI) pathway, which can increase the Ca2+ concentration by releasing Ca2+ from intracel-lular stores, and increase the transmembrane influx of Ca2+ from outside the cell at the expense of K+ efflux, which is regulated by K+ channels. In contrast, these K+ channels are not present in mouse T cells (Koo et al., 1997), suggesting that their ionic concentrations are regulated differently.

Stimulation of CD4 helper T cells results in their differentiation into either Th1 or Th2 cells, which are phenotypically identified based upon their cytokine production profile. This differentiation process is controlled by the strength of Ag stimulation, the cytokine microenvironment, and B-7 receptor family costimulation. IFN-« can induce CD4+ T cell differentiation toward a Th1 phenotype as well as the activation of STAT4 cascade in humans, but fails to do so in mice. This is mainly because an adaptor protein involved in the IFN-a receptor complex, STAT2, has a different C-terminal in the human and mouse, resulting in mice not being able to transduce the stimulatory signal to STAT-4 (Farrar et al., 2000). In contrast, TCR stimulation plus IL-10 is sufficient to induce Th1 differentiation in the mouse CD4+ T cells, but has little effect on human CD4+ T cells

(Battaglia et al., 2004). The immunosuppressive cytokine IL-10 is secreted by mouse Th2 cells, but it is secreted by both Th1 and Th2 T cells in humans (Del Prete et al., 1993). This indicates that, in humans, the Th1/Th2 classification based on their cytokine production is less clear and exclusive.

Recently, data has emerged showing that a new type of regulatory T cell exists in addition to the Th-1/Th-2 subsets. The CD4+CD25+ regulatory T cell (T-reg) is a T cell subset expressing both CD4 and IL-2Ra on its surface, and requires only low levels of TCR and IL-2 signals to respond robustly. The function of T-reg cells is unique and important to T cell activation. It can suppress the activation of CD4+CD25~ T cells, CD8+ T cells, natural killer (NK) cells, and negatively regulate cytokine production by target cells. The amount and surface phenotype of T-reg cells are different between humans and mice. In mice, CD25 expression is relatively high and about 10% of CD4+ T cells are T-reg cells, whereas in humans, CD4+CD25high occupies only 2 to 4% of CD4+ T cells. Some other cell surface receptors expressed on mouse T-reg cells like CD62L and CD38 are absent in human T-reg cells as well. The activity of T-reg cells is important in autoimmune disease; thus, differences in CD25 expression in humans and mice may result in quantitative differences in stopping the activity of T cells bearing self-Ag (Baecher-Allan et al., 2004).

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

Get My Free Ebook

Post a comment