Studies on the loss of naïve T cells
Richard Jefferys, TAG
A recent post covered a review by Beth Jamieson and Tammy Rickabaugh describing the parallel effects of HIV infection and aging on the pool of naïve T cells in humans. 
Three recent papers address different aspects of naïve T cell loss, including the first study to document a decrease in this population in people with chronic hepatitis C infection.
In PLoS One, Beth Jamieson’s group reports on a study of naïve CD4 T cell levels in younger (20-32 years) and older (39-58 years) individuals with untreated HIV infection, compared to age-matched HIV-negative controls. 
The researchers use a cell surface marker named CD31 to discriminate between naïve CD4 T cells that have recently been produced by the thymus (CD31+) and those that have proliferated in the circulation (CD31-). Consistent with previous studies, HIV infection had a strong effect on naïve CD4 T cell levels that was additive to that seen in aging; the absolute number of CD31+ naïve CD4 T cells in the younger individuals mirrored those measured in HIV-negative controls who were 17-28 years older. While both HIV infection and aging were associated with declines in CD31+ naïve CD4 T cell numbers, loss of CD31- naïve CD4 T cells was only observed HIV infection; in this case the effect was independent of aging as the absolute loss was similar in both the younger and older HIV-positive participants. In a separate longitudinal analysis of the effects of antiretroviral therapy, CD31+ naïve CD4 T cells achieved levels comparable to age-matched controls after two years of treatment. However, CD31- naïve CD4 T cell levels remained significantly reduced.
The researchers also evaluate telomere lengths in both naïve CD4 T cell subsets, finding them to be reduced both as a result of HIV infection and aging; as was seen for CD31+ naïve CD4 T cell numbers, the effects were additive. Jamieson and colleagues conclude by suggesting that their results likely explain why disease progression occurs more rapidly among HIV-positive individuals over the age of 50, because this older population already has reduced numbers of naïve CD4 T cells, making the impact of HIV infection more severe. They also note that incomplete recovery of naïve CD4 T cells may play a role in increasing the risk of aging-associated diseases in people with HIV.
One commonly cited causative mechanism of naïve T cell depletion in HIV is the persistent activation of these cells, which leads to their differentiation into memory cells. Another contributing factor is lymphoid tissue fibrosis (a type of scarring damage associated with immune activation & inflammation). Naïve T cells continually recirculate through lymphoid tissue and depend on signals received in that environment for their survival.
A recent study by Ming Zeng and colleagues delves into this link between lymphoid tissue fibrosis and naïve T cell loss in both SIV and HIV infection. 
The researchers find that fibroblastic reticular cells (FRC)–which form the pathways along which T cells travel in lymph nodes–are the major source of IL-7, a cytokine essential for naïve T cell survival. Fibrotic damage (measured by the accumulation of collagen) is shown to disrupt the FRC network and therefore impede the ability of T cells to access IL-7, causing an increase in T cell apoptosis. Both naïve CD4 and CD8 T cells are affected. Additional studies reveal that the loss of T cells in turn exacerbates the damage to FRCs by reducing the production of a cytokine called lymphotoxin-É¿, which is vital for maintaining FRC networks. The results suggest that there is a vicious cycle in which fibrosis damages FRCs, which causes T cell loss, which then further exacerbates FRC loss.
Continuing their investigative work, Zeng et al look for a source of collagen and find that production of the cytokine TGF-beta by regulatory T cells is increased in HIV, and TGF-beta induces collagen production by fibroblasts. In lab experiments, the antifibrotic drug pirfenidone blocks TGF-beta signaling and reduces collagen production, leading the researchers to conclude that this drug may deserve consideration as an adjunctive therapy for promoting immune reconstitution in HIV.
Lastly, a study published in the 1st March issue of the Journal of Infectious Diseases demonstrates that another persistent chronic infection, hepatitis C, can accelerate naïve CD4 T cell loss. The authors conclude that their findings provide an explanation for the reduced response to vaccinations observed in people with chronic HCV. 
Source: TAG basic science blog (17 Mar 2011)
- Jamieson B and Rickabaugh T. A challenge for the future: aging and HIV infection. Immunol Res. 2010 Aug 24. [Epub ahead of print]
- Rickabaugh TM et al. The Dual Impact of HIV-1 Infection and Aging on Naïve CD4 T-Cells: Additive and Distinct Patterns of Impairment. PLoS One. 2011 Jan 26;6(1):e16459.
- Zeng M et al. Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 . J Clin Invest. doi:10.1172/JCI45157.
- Yonkers NL et al. Reduced Naive CD4 T Cell Numbers and Impaired Induction of CD27 in Response to T Cell Receptor Stimulation Reflect a State of Immune Activation in Chronic Hepatitis C Virus Infection. J Infect Dis. 2011 Mar;203(5):635-45. Epub 2011 Jan 10.