CRITERIOS PARA LA SELECCIÓN DE UN MOTOR COMO

T cells play a major role in immune responses, performing both regulatory and direct effector functions. T cells can be divided into two major phenotypically distinct subsets depending on whether they express the cell surface marker CD4 or CDS. Classic T cell subsets are CD4^ and CDS^ cells. CD4^ cells recognize antigen in association with MHC class II molecules and play a role in the immune response, providing help for antibody production by B cells and coordinating events that lead to delayed-type hypersensitivity. CDS^ cells recognize antigen in association with MHC class I molecules and are responsible for cytotoxicity and immunological surveillance (Konig et al., 1992; Cammarota et a l, 1992). T cells can also be categorized according to their developmental stage. Memory cells bear the CD29 marker or CD45RO, whereas naïve cells are CD45RA positive. CD25 or IL- 2 receptors are expressed on the surface of activated T cells.

Functionally CD4^ and CD8^ T cell can be classified as either helper T cells (Th) or cytotoxic T cells (Tc). Th cells are generally CD4^ cells and involved in providing help for antibody synthesis. T cell differentiation is crucial to the outcome of an immune response. Early in the process of activation, T cells are committed to develop into one of several functionally distinct effector subsets, including Thl, Th2, ThO, Th3. Thl cells secrete mainly IL-2, interferon gamma (IFN-y) and TNF-a, whereas Th2 cells secrete predominantly IL-4, IL-5 and IL-13. These two subsets appear to regulate each other. IFN-y inhibits the differentiation and proliferation of Th2 cells. On the other hand, IL-4 and IL-10

been shown to secrete both types of cytokines (Firestein et al., 1989), while T-cells producing high levels o f TGF-p have been named Th3 (Chen et al, 1994; Weiner, 2001;). T cell differentiation is regulated by the local microenvironment. Hence, the nature o f the antigens encountered by the T cell, the expression o f costimulatory molecules and the cytokines secreted by the antigen presenting cells (APC) drive T cell differentiation. In vitro,

IL-12 drives Thl differentiation, whereas IL-4 promotes Th2 differentiation (Figure 1.4).

TL-12

Thl responses

responses

Figure 1.4 Thl/Th2 differentiation. From Escoubet-Lozach et al. (2002)

Tr cells (Table 1.1) are enriched within the 10% o f peripheral CD4^ cells that express CD25. The defining feature o f CD4^CD25^ Tr cells in both mice and humans is their ability to

inhibit the proliferation of other T cell populations in vitro (Maloy and Powrie, 2001). So far, Foxp3 is the gene which closely correlates with CD4^25^' Tr cells (Ramsdell 2003).

Table 1.1. Different types of regulatory T cells From Umetsu et al. (2003)

Regulatory cell Cytokines produced Cell surface markers Others T h l Th3 Trl Tr C D25' N K T IFN-y, IL-2 TGF-P IL-10 IL-10 IL-10, TGF-P IL-4, IL-13, IFN-y, restricted TCR repertoire CD4 CD4 CD4 CD4 CD4, CD25, GITR, FoxpS CD4 or double negative (neither CD4 or CDS)

Thl cells can inhibit the developm ent o f Th2 cells but not the function o f Th2 effector cells. (Hansen et al., 1999) Ty3 cells appear to develop during oral

tolerance and production o f TGF-P (Chen e /a /., 1994)

T fl cells develop during culture with IL-10 and produce IL-10 (Groux et al.,\991)

Tr cells develop during culture with DCs producing IL-10 (Roncarolo et al., 2001)

CD25^ cells are naturally occurring regulatory cells that are involved in preventing autoimmune disease (Sakaguchi et al., 1995)

N K T cells are naturally occurring cells that rapidly produce large quantities o f cytokines. N K T cells regulate the developm ent o f autoimmune disease (M iyam oto et al., 2001)

Because IgE synthesis and eosinophilia are hallmarks o f allergic disease, it has been postulated that CAED-associated inflammation is mediated by a Th2 response. Th2 cells recognize the allergen peptides and are able to release cytokines that are responsible for IgE antibody production by B cells (IL-4 and IL-13), mast cell growth (IL-4, IL-10, developmental factor c-KIT ligand (stem-cell factor, SCF); TGF-p and IL-6)(Hogaboam et al., 1998; Funaba et al., 2003; Ishida et al., 2003; Gyotoku et al., 2001), eosinophil accumulation (IL-5), and mucus hyperproduction (IL-9, IL-13) (Kawakami and Galli, 2002; Bonini et al., 1995; Bielory et al., 2002). In the normal conjunctiva, most of the T cells are naïve and are low in numbers, but in the chronic allergic conditions (AKC, VKC, GPC), there is an increase in CD4 ^ memory T cells. In VKC and GPC, 50% of T cells co-express CD45RO and CD45RA. AKC is associated with systemic atopy, and those conjunctival T cells can be recruited from circulating specific memory T cells (Metz et al., 1996). A study reported that CD4^ CD25^ T cells modulate the Thl and Th2 cell balance towards Th2 cells and thus upregulate Th2 cell-mediated allergic inflammation in the airways (Suto et al., 2001). It has been found that the CD25^ cells were the most numerous and CD25^ expression strongly correlated with the number of CD3^T cells infiltrating the conjunctiva of patients with VKC (Abu El-Asrar et al., 2002). However this data was obtained by immunohistochemistry and the function of these cells has not been investigated.