Ahorro en la cuota de emisiones de GEI del sector transporte en el periodo

A vaccine which promotes a robust memory B cell antibody-based response to the surface proteins of one strain of influenza is likely to be ineffective for a strain encountered the next season expressing different surface proteins (267). However, there are several internal viral proteins that are highly conserved among influenza viruses, and therefore do not experience the drift and shift problems seen with the external proteins. Although these proteins do not generate an effective antibody response because they are not exposed on the surface of the virus and, therefore, not accessible to B cells, influenza-specific T cells can recognize these proteins. Memory T cells generated during a primary influenza infection can target these internal proteins common to influenza strains, making them effective against encounters with heterologous virus stains. The ability to generate functional memory T cells, either during primary infection or by vaccination, has proven to be protective against potentially lethal influenza strains exhibiting completely different surface antigens (268). Indeed, exploiting this know capability of memory CD8+ _{T cells to recognize a broad range of} heterosubtypic viruses is currently a hot focus of vaccine development (269,270)

H.3.1. Memory CD8+ T cell Generation

CD8+ T cell responses have evolved to specifically eliminate pathogens and to protect against reinfection (271,272). The generation of long term immunity is dependent on the formation a pool of long-lived memory T cells. During infection with influenza A/PR/8 in

42

a rodent model, lack of CD8+ _{cells results in decreased viral clearance and eventual} morbidity (273). Initial recognition by a naïve CD8+ _{T cell of a foreign peptide/major} histocompatibility complex (MHC) class I on an antigen presenting cell (APC) results in rapid clonal expansion and gain of effector function. The extent of the influenza-specific CD8+ effector T cell response can be related to viral load which is, presumably, reflective of antigen load on DCs (274). As in the primary response, upon contact with an infected cell, influenza-specific memory CD8+ T cells act to inhibit viral replication and to destroy virally infected cells. These functions are achieved through the secretion of IFNγ and perforin/granzyme B as well as Fas/FasL pathway (246). Following infection, activation and expansion of naive influenza-specific CD8+ _{T cells occur in the draining LN (242,244) These} cells then migrate and localize to the lungs and infected airway epithelium where they exert their effector functions, producing antiviral cytokines and lysing target cells presenting viral determinants for which they bear a specific T-cell receptor (242,244,247)

Following viral clearance, the activated effector T cells are no longer needed and activated short-lived effector cells (SLEC) responding to the primary infection are eliminated from the antigen-specific population (237,275). Contraction of activated CD8+ T cells results in a pool of memory cells representing ~5 to 10% of effector CD8+ T cells found at the peak of expansion during primary infection (276-278). Cessation of the antigenic stimulus prompts the activated effector cells to undergo activation-induced cell death (AICD). This apoptosis can be induced by a number of mechanisms including interaction of the Fas molecule on the T cell surface with the Fas ligand, a member of the TNF family of cytokines (237). Downregulation of the protective Bcl-2 gene during activation of effector CD8+ T cells leaves the cells vulnerable to Fas/caspase contraction, mainly mediated through the proapoptotic molecule Bim. Activation of Bim leads to proapoptotic factors being released from the inner mitochondrial membrane into the cytosol, such as cytochrome c which contributes to the formation of the apoptosome and the subsequent activation of the caspase cascade (237). T

43

44

cells lacking Bim undergo normal expansion but are more resistant to contraction (279). Effector CD8+ _{T cells with increased Bim and reduced Bcl-2 expression, generated through} a knockout of the Id2 transcription factor, have increased contraction following the effector phase (280). The extent of contraction can be modulated by the extent of infection duration and resulting inflammatory signals. Short-term pathogen infection decreases the size of the resultant memory pool while insufficient duration or quality of TCR signal or other signals can lead to increased contraction and a reduction of the memory cell pool (276,278,281).

H.3.1.1. Delineation of Memory versus Primary Effector T cells (Figure 1.8)

Recent studies of the generation of long-term immunity and efficacious vaccination against viral agents have begun to focus on the generation of large numbers of long-lived, antigen-specific CD8+ memory T cells. From these studies, it has become apparent that generation of function CD8+ memory T cells requires a “balancing act” between memory cell potential and terminal differentiation into full effector T cells (282). Antigen density on the dendritic cell and time of contact with the APC, costimulatory factors and signals and levels of inflammatory cytokines could play a role in programming the development of memory potential (283). The lack of an early definitive marker that can distinguish an effector cell from a memory cell hampers a clear definition of when bona fide memory cells are generated during a CD8+ _{T-cell response; however, studies have shown altered T cell} responses can lead to changes in memory cell populations and function. Timing, location and amount of exposure to antigen during CD8+ T cell development appear to be very important.

Memory CD8+ T cells are preferentially established in draining lymph nodes at early (days 1-3) and late (day 28) but not acute (days 7-10) time-points after influenza infection. The least efficient population for transfer of memory is the highly activated day 8-10 population (284). While it is clear that early and late events also shape CD8+ T-cell memory,

45

46