By Simon Noble, PhD
Chemokines Enhance CD8+ T-cell Memory
CD8+ T cells are often thought of as the frontline weaponry in the battle to fend off pathogens and malignant cells, but crucially they require helper activity from CD4+ T cells. This help is especially important in assisting the development of long-term CD8+ T-cell memory. The antigenic ligands for the CD8+ and CD4+ T cells involved in help-dependent responses must be co-presented by the same antigen-presenting dendritic cell (DC). Precisely how this is accomplished has not been fully understood.
Two different models have been proposed to explain how this holy trinity of DC, CD8+, and CD4+ T cell manage to pass the relevant signals between them. The first suggests that the two T cell types bind simultaneously to a single DC and that local cytokine production or direct interaction promote their cooperation. But since T cells specific for any particular antigen are rare in the context of the naïve T cell pool, it has been argued that there would be a very low probability of this happening. The second model therefore proposes that the DC-CD4+ T-cell interaction induces differentiation of the DC (called 'licensing') that then supports subsequent CD8+ T-cell priming.
Now a group of researchers led by Ron Germain provide convincing evidence that the chemokines MIP-1a and MIP-1b (also known as CCL3 and CCL4) are key players in actively guiding the recruitment of CD8+ T cells to join the DC-CD4+ T cell interaction (Nature 440, 890, 2006). They transferred transgenic CD8+ and CD4+ T cells specific for OVA antigen into immunocompetent mice, immunized the mice subcutaneously with either OVA or an irrelevant antigen in opposite flanks, and then compared the distribution of CD8+ T cells in the two draining lymph nodes. They found a significantly greater accumulation of the CD8+ T cells in the lymph node on the OVA-immunized side.
The researchers then used intravital 2-photon microscopy of intact lymph nodes in living animals and fluorescently dyed T cells and DCs to see if this increased accumulation was characterized by enhanced direct interactions between the cell types. They found that when CD4+ T cells were present, CD8+ T cells were much more likely to interact with OVA-pulsed DCs as opposed to unpulsed DCs, suggesting that the CD4+ T cells were augmenting the interaction specifically with DCs presenting cognate antigen. The researchers suspected that this process might be chemokine dependent and so injected the mice with various chemokine-blocking antibodies; antibodies against MIP-1a and MIP-1b reduced the accumulation of CD8+ T cells in the lymph node whereas antibodies against other chemokines had no effect.
The researchers then looked at the functional significance of these findings. MIP-1a- and MIP-1b-blocking antibodies eliminated the enhancing effect of CD4+ T cells on both the number and the effector activity of CD8+ memory T cells measured several weeks later. However, blockade of these chemokines did not affect the acute expansion or the acquisition of effector functions of CD8+ T cells, suggesting that they are not simply augmenting co-stimulatory signals involved in CD8+ T-cell activation or other trafficking events.
The findings increase fundamental understanding of the immune system, indicating that inflammation leads to CCR5 expression by naïve CD8+ T cells that then enables them to be actively attracted to sites of productive DC-CD4+ T cell interaction. The research could open up new avenues to augmenting CD8+ T-cell memory in vaccination strategies, perhaps using chemokines as adjuvants.
HIV Nef Strikes Again
A huge assortment of effector functions have been attributed to HIV's Nef protein, and now it seems another can be added. It has been reported that Nef is required for high levels of viral replication, for progression to AIDS in the infected host, helps in immune escape, affects numerous cellular signaling pathways, increases infectivity of progeny virions, downregulates cell surface expression of important immune molecules and helps immune evasion, helps prevent infected cells from apoptosis, and helps facilitate the infection of T cells. New research from a team led by Andrea Cerutti (Nat. Immunol. 7, 302, 2006) now suggests that Nef can also affect the antibody response against HIV by inhibiting immunoglobulin class switching, thereby preventing the maturation of the antibody response.
Class switch recombination is a process that occurs after B lymphocytes have been activated by CD4+ T cells through CD154 and the cytokines interleukin (IL)-4 and IL-10 and they migrate to the germinal centers of secondary lymphoid organs. This class switching substitutes the heavy-chain constant region of IgM and IgD with that of IgG, IgA, or IgE, giving the new classes of antibodies different effector functions that enhance their ability to counteract pathogens; IgG and IgA can neutralize viruses both systemically and at mucosal entry sites.
It is known that the humoral response to HIV is defective and that it is improved by antiretroviral therapy, and that B cells are intrinsically poorly responsive to CD4+ T-cell help in HIV infection. However, HIV does not infect B cells so how are these effects mediated? Nef, like Tat, is secreted extracellularly, and the researchers first showed that Nef can accumulate in B cells both in vivo and in vitro. This intracellular accumulation interfered with a number of signaling pathways by increasing the regulatory proteins IκBa, SOCS1, and SOCS3, which in turn blocked signaling through NF-κB and STAT and, ultimately, CD154 (also known as CD40L), IL-4, and IL-10, resulting in inhibition of class switch recombination.
The researchers only demonstrate these effects in vitro and it will be important to see if the findings hold up in HIV-infected individuals and monkey models of infection. And since Nef has been included in some vaccine candidates, what are the implications in light of these new findings? The authors end by speculating that Nef-blocking agents might be useful in improving the antibody response to HIV.