Pf4

CFSE Fluorescence

Culture Condition

CFSE-labeled CD4+CD25-

Co-culture

CFSE-labeled CD4+CD25+

Co-culture

FIGURE 5 PF4 induces proliferation of CD4+CD25+ Tr cells and impairs their ability to suppress the response of CD4+CD25~ T cells to anti-CD3. CFSE labeled CD4+CD25~ T cells were cultured alone (A-B) or with an equal number of unlabeled CD4+CD25+ Tr cells (C-D). In the converse experiment, CFSE labeled CD4+CD25+ Tr cells were cultured alone (E-F) or with an equal number of unlabeled CD4+CD25~ T cells (G-H). Dashed lines (shown only on panel A) indicate the boundaries of each division cycle. The numbers appearing above each peak (0-5) denote each division population, with the undivided T cells (0) residing in the rightmost peak, and the T cells that have divided five times (5) residing in the leftmost peak. The leftmost peak represents unlabeled CD4+CD25+ (C and d) and CD4+CD25" T cells (G and H). The percent divided (% Div.) represents the portion of the original CFSE labeled T-cell population induced into cell division. Abbreviations: CFSE, carboxyfluorescein diacetate succinimidyl ester; PF4, platelet factor 4; Tr, regulatory cells; T, cells. Source: From Liu et al., 2005.

greater risk to produce PF4-heparin-specific antibodies and to develop HIT, if rechallenged with heparin. However, Cadroy et al. (1994) described a patient with a history of HIT, who mounted a brisk IgM response when challenged again with UFH 3yr later. A report by Warkentin and Kelton (2001) suggests that there is no anamnestic immune response in HIT (i.e., patients either have typical" HIT [onset at days 5-10] or "rapid" HIT, the latter apparently caused by residual circulating HIT antibodies rather than a secondary immune response). Furthermore, HIT did not necessarily recur in patients who were exposed to heparin a second time.

Our findings provide the first evidence that the CXC chemokine PF4 can interfere with Tr-suppressive capacity. We hypothesize that in HIT, PF4 is not only the target for the antibody (when complexed with heparin) but is also a modulator of T-cell activation.

We propose that the modulatory effect of PF4 on CD4+CD25+ Tr cells is not a "physiological" effect on the immune system homeostasis but is rather a pathologic complication of heparin therapy, since heparin scavenges PF4 from EC GAGs and directly from circulating platelets (Zucker, 1975). Moreover, platelet activation that occurs during and after specific invasive procedures associated with heparin administration (such as cardiopulmonary bypass) leads to increased PF4 release into the circulation (Wan et al., 1997). Therefore, a transient impairment of the Tr suppressor activity might be postulated in otherwise healthy individuals experiencing acute platelet destruction, thus providing a possible explanation for why different patient groups exposed to heparin become sensitized at different rates (Visentin et al., 1996; Yamamoto et al., 1996).

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