Longitudinal Analysis of the Kinetics of CD8 T Cells

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Kinetics of CD8 T cell expansion and differentiation in the blood and secondary lymphoid organs during L. infantum infection of rhesus macaques.
Previously, we reported that rhesus macaques infected with L. infantum were able to contain the parasites in visceral compartments (liver and spleen), during the first weeks after inoculation. However, progression to the chronic phase of infection was associated with a relapse of the parasite load in these organs as well as with a substantial increase in parasite burden in the blood, bone marrow and lymph nodes (ref, PPATHOGENS). We examined the same animals for a longitudinal analysis of the CD8 T cell response in the blood and secondary lymphoid organs during the acute and chronic phase of L. infantum infection.
The percentage of CD8 T cells in the blood or lymph nodes did not change significantly during the course of our experiments (Fig. 1A-B). In contrast, the splenic CD8 T cell pool expanded significantly after infection, from 16.9 ± 1.8 % of the total splenocytes in naïve animals, to 44.9 ± 3.6 % at day 28 post-infection (pi); a frequency that persisted elevated at the chronic phase (day 250 pi) (Fig 1C). In absolute numbers, it represented a 4-fold increase in the size of the splenic CD8 T cell population at days 28 and 250 pi, as compared with non-infected animals (Fig. 1 D).
The majority of blood CD8 T cells presented a differentiated phenotype, even in non-infected animals, as noted by low expression of CD62L (Fig. 1E-F). Hence, effector memory (CD62L- CD45RA-) or terminally differentiated (CD62L- CD45RA+) CD8 T cells predominated in the blood, regardless of pathogen presence (Fig. 1E-F). The relative frequencies of these subsets remained relatively constant throughout the e...

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...however, in the expression of the inhibitory receptor LAG-3 in splenic CD8 T cells at days 28 and 250 pi, as compared with non-infected animals (Fig. 6A-B). In lymph nodes, we failed to detect any significant increase in the expression of the two inhibitory receptors analysed (Fig. 6C-D). Nevertheless, LAG-3 expression tended to increase progressively as the infection advanced towards the chronic phase Fig. 6C-D).
Taken together, our data suggests that chronic CD8 T cell loss of function in the spleens of rhesus macaques infected with L. infantum is related with increased expression of inhibitory receptors, particularly LAG-3. Furthermore, the functional exhaustion of splenic CD8 T cells is coincident with parasite dissemination in the organism (ref. PPATHOGENS), suggesting that effector CD8 T cells are important to contain the infection and limit parasite spread.

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