Chemokines and graft-versus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 396

“mature” donor T cells contaminating the stem cell graft are responsible for
initiating GVHD, marrow-derived donor cells of the myeloid lineage also
have a significant role in systemic inflammation and target tissue injury.
Recent data suggest that the effector functions of myeloid and lymphoid
cells synergize to cause target organ damage [7] , and the contribution of
donor myeloid or “accessory” cells is primarily through the secretion of
inflammatory cytokines and chemokines [7,8] . Thus, the effects of chemo-
kines on hematopoietic reconstitution may influence HCT outcomes via
both GVHD-independent and GVHD-dependent mechanisms.

T-cell activation

The second stage of GVHD is dependent upon the recognition of host allo-
antigens by donor T cells. Specifically, studies have shown that in the murine
transplant model, naïve T cells are critical to the induction of acute GVHD,
whereas T cells expressing memory markers such as CD44 or the absence
of CD62L are not [27,28] . Recent data suggest that chemokines may have
profound effects during this stage of GVHD. For example, the proinflamma-
tory environment established early after HCT facilitates the maturation of
host dendritic cells (DCs) and other APCs. DC maturation results in repres-
sion of endocytic activity and enhanced expression of MHC, adhesion, and
costimulatory molecules. A switch in chemokine receptor usage involving
the downregulation of inflammatory chemokine receptors and an upreg-
ulation of receptors for homeostatic chemokines such as CXCR4, CCR4,
and CCR7 also occurs. This pivotal switch makes the DC more sensitive to
the CCR7 ligands CCL21 and CCL19 (expressed by lymphatic endothelial
cells and in T-cell zones of lymphoid organs) and helps facilitate the move-
ment of matured DCs from the site of antigen capture back to the lymph
node or site of antigen presentation [16] . CCR7 may be necessary for an
optimal alloimmune response. CCR7 knockout mice have delayed T and B
responses and severe defects in their lymphoid architecture [29] . Naïve and
central memory T cells express CCR7, which has been shown to be critical
to the development of acute GVHD [30] . Mice receiving HCT with T cells
deficient in CCR7 developed significantly less GVHD in a variety of strain
combinations. CCR7 −/− T cells demonstrated an impaired capacity to traffic
to lymph nodes and to interact with splenic DCs, but did retain their capac-
ity to generate protective graft-versus-leukemia (GVL) effects. Importantly,
CCR7-deficient regulatory T cells (Tregs) were able to modulate GVHD
when infused before CCR7 +/+ conventional T cells.

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Using CCR7 and CD45 as markers to detect naïve, central memory, or effec-
tor memory T cells in HCT recipients, Yakoub-Agha and colleagues found
that T cells expressing CD4 and CCR7 were associated with the incidence
and severity of acute GVHD, but no association was observed between the
expression of CCR7 and the incidence or severity of chronic GVHD [31] .

Chemokines also contribute to donor T-cell activation and differentiation
(reviewed in [13,18] ). For example, CXCL12 (SDF-1α) has been shown to
promote CD4 + T-cell responses and T-cell clones can be directly stimulated
by CCL5 and other chemokines in vitro. Specifically, CCL5 and CCL3 con-
tribute to polyclonal and antigen-specific activation of helper and cyto-
toxic T cells and can enhance APC functions [32] . In addition, CCR1:CCL5