Cognate CD4 help is essential for the reactivation and expansion of CD8 memory T cells directed against the hematopoietic cell–specific dominant minor histocompatibility antigen, H60

Abstract

In contrast to previous notions of the help-independency of memory CD8 T cells during secondary expansion, here we show that CD4 help is indispensable for the re-expansion of once-helped memory CD8 T cells, using a hematopoietic cellspecific dominant minor histocompatibility (H) antigen, H60, as a model antigen. H60-specific memory CD8 T cells generated during a helped primary response vigorously expanded only when rechallenged under helped conditions. The help requirement for an optimal secondary response was confirmed by a reduction in peak size by CD4 depletion, and was reproduced after skin transplantation. Helpless conditions or noncognate separate help during the secondary response resulted in a significant reduction in the peak size and different response kinetics. Providing CD4 help again during a tertiary challenge restored robust memory expansion; however, the repeated deprivation of help further reduced clonal expansion. Adoptively transferred memory CD8 T cells did not proliferate in CD40L ؊/؊ hosts. In the CD40 ؊/؊ hosts, marginal memory expansion was detected after priming with male H60 cells but was completely abolished by priming with peptideloaded CD40 ؊/؊ cells, suggesting the essential role of CD40 and CD40L in memory responses. These results provide insight into the control of minor H antigenspecific CD8 T-cell responses, to maximize the graft-versus-leukemia response. IntroductionMinor histocompatibility (H) antigens are naturally processed peptide fragments derived from proteins with polymorphisms that generate differential major histocompatibility complex (MHC)-presenting epitopes. 1 They are recognized as foreign during allotransplantation between MHC-matched subjects, resulting in the induction of specific CD4 and CD8 T-cell responses that can lead to life-threatening graft-versus-host disease (GVHD); however, they have also been found to exert a graft-versus-leukemia (GVL) effect. 2 Therefore, characterization of the immune response to minor H antigens with specific expression on hematopoietic lineage cells is necessary to apply the minor H antigen-specific T-cell response most productively toward eradicating malignant leukemic cells while suppressing GVHD.Allo-reactive CD8 T cells are major effectors of rejection after allogeneic transplantation. The CD8 T-cell response to antigen exposure generally involves an initial expansion phase followed by a contraction phase and a memory phase. [3][4][5] During this process, help conferred by CD4 T cells is essential for generating the CD8 T-cell response to noninflammatory Th-dependent antigens, such as minor H antigens, although the timing and mechanism of delivery of this help to CD8 T cells is controversial. CD40 and CD40L are believed to be major mediators of CD4 help. Signaling through CD40 via an interaction with CD40L expressed on activated CD4 T cells activates antigen-presenting cells (APCs), which subsequently increases their antigen presentation and costimulatory capacity, priming CD8 T cells directly. [6][7][8][9] In contrast to n...

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