Underestimating the (CD4 T Cell) Help

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Underestimating the (CD4 T Cell) Help
Following on from the recent post about the importance of virus-specific CD4 T cells in controlling SIV, another new paper adds to the evidence that they also play an important role in HIV infection. Conducted by the laboratory of Hendrik Streeck at the Ragon Institute in collaboration with David Heckerman at Microsoft, the study "represents the first comprehensive analysis conducted at the population level to identify HIV-specific CD4 T cell responses to individual HIV protein subunits and peptides and to elucidate the immunodominance profile of these responses in a large cohort of HIV-controllers and progressors." Given that there has long been an appreciation of the importance of CD4 T cells in immunity against many pathogens, it seems quite remarkable that it has taken until 2011 for such a study to be undertaken. The authors themselves note: "surprisingly little is known about the presence of these responses in the setting of HIV infection."

The main findings include:

1.Individuals controlling HIV replication in the absence of treatment have HIV-specific CD4 T cell responses targeting a greater number of peptides on average compared to those with progressive infection (10.9 vs. 6.6).

2.The breadth of the HIV-specific CD4 T cell response was inversely correlated with viral load, and this association was driven by CD4 T cells targeting the Gag protein.
The magnitude of the CD4 T cell response to Gag showed a strong inverse correlation with viral load.

3.Responses to Gag were associated with low viral load whereas responses to Env were linked to high viral load, and the ratio between Gag and Env responses was strongly correlated with viral load control: the lowest mean Env/Gag ratio was found in elite controllers (0.20) while the highest mean ratio was in progressors with high viral loads (2.63).

4.CD4 T cell responses to three highly conserved Gag epitopes were identified as being strongly predictive of immunological control of HIV replication, independently of host HLA types.

The authors conclude: "Taken together, these data are consistent with our hypothesis that HIV-specific CD4 T cell responses are likely to be beneficial in the control of HIV during chronic infection."

In a separate paper just published online by the Journal of Immunology, Daniel McDermott and Steven Varga report new data on virus-specific CD4 T cells in the context of LCMV infection in mice.
The researchers have developed a new method to assess the magnitude of the CD4 T cell response that uses cell surface markers (CD11a and CD49d) as opposed to previously used techniques that rely on measuring responses to specific antigens.

By employing this approach, they are able to demonstrate that the CD4 T cell response to LCMV is much larger than prior studies suggested, comprising up to 50% of peripheral blood CD4 T cells in C57BL/6 mice at the peak (versus the 10% estimated previously in the same mouse strain).

In the subsequent memory phase of the immune response, approximately 6.5% of CD4 T cells were LCMV-specific, also considerably higher than prior estimates. The researchers note, however, that the genetic background of the mice has a large influence; in the BALB/c mouse strain for example, the peak response was lower at around 15%.

The overall conclusion of the authors is that current methods have significantly underestimated the total magnitude of pathogen-specific CD4 T cell responses; they posit that, in contrast, their new approach can “accurately track the kinetics and magnitude of the entire endogenous CD4 T cell response from the expansion phase into memory.”

see link: http://tagbasicscienceproject.ty ... d4-t-cell-help.html