Secondary /anamnestic / booster immune responses

SECONDARY, ANAMNESTIC OR BOOSTER IMMUNE RESPONSES : the immune response occurring on the second and subsequent exposures to an antigen; compared to a primary response, the lag period is shorter, the peak antibody titer is higher and lasts longer, IgG production predominates, the antibodies produced have a higher affinity for the antigen, and a much smaller dose of the antigen is required to initiate the response (not for T-independent antigens !) (see also primary immune response

)

activation of memory B cells : upon rechallenge with antigen, memory B cells reestablish germinal centers and can undergo up to an estimated 20 additional rounds of replication^ref. IgGs and IgAs with higher affinity are produced within 1÷3 days (peak at day 3÷5) and reach titres 100÷1000 times higher than in primary response.
activation of memory T cells (late in primary response and during memory response) in peripheral tissues requires just 50 peptide-MHC complexes (pMHC) per APC (instead of 300 for naive T cells)^ref :

obliged signals (if absent => clonal anergy; if present withour TcR-MHC binding => no T-cell activation occurs) :

CD27 --- CD70 / 27L
MIC family (MICA, MICB) --- NKG2D (on NK cells, TcRgd⁺ T cells, CD8⁺TcRab⁺T cells, and activated macrophages)

facultative (increased survival) signals :

CD49d CD29 / VLA-4 / a₄b₁ integrin --- CD106 / VCAM-1 / INCAM-110
LIGHT / TL5 --- DcR3 / TRAIL-R6 (soluble)

downregulatory signals

CD152 / CTLA-4 --- B7 (i.e. CD80 / B7-1 (preferential binding) and CD86 / B.7.2 : binding avidity 20- to 50-fold higher than for CD28) interaction results in reduced downstream TcR signaling (activation of PI(3)K, SHP-1 / PTPN6, SHP-2, and PP2A ; inhibition of ERKs, JNK, lipid raft assembly and CD3-mediated phosphorylation of the positive regulatory ZAP70 Y319 site), increased synthesis of TGF-b (in CD4⁺ T cells), impaired IL-2 production and cell cycle progression => clonal anergy. CTLA-4 blockade abrogates the induction of peripheral tolerance, enhances antitumour responses and exacerbates autoimmune disease : knockout mice develop a fatal lymphoproliferative disease. Thus, CTLA-4 may preferentially dampen pathologic immune responses to self proteins while permitting protective immunity to foreign antigens. CD86 expression in B cells is upregulated by stimulation of BcR or b₂-AR .
CD223 / LAG-3 (on activated CD4⁺ and CD8⁺ T cells and activated NK cells) -- MHC class II : it competes with CD4 for MHC class II binding on APC surface as it has much higher affinity than CD4
PEST-domain-enriched tyrosine phosphatase (PEP) / PTPN8 dampens the response of effector/memory T cells to TcR stimulation by dephosphorylating a crucial regulatory tyrosine residue on Lck^ref. Blocking the activity of PEP might enhance the response to vaccination

CCL5

T_h1 cells

CD8ab⁺ cytolytic cells

naive

CD4⁺ memory T cells activation : the mature synapse forms by 5 to 15 minutes after initial APC contact and remains for > 90 minutes. In the memory T cells only, TcRs are constitutively associated with lipid rafts , which might account for the more rapid formation of the mature synapse together with the fact that LCK is still active when it moves into the cSMAC of the mature synapse due to the observed presence of the tyrosine phosphatase CD45 / B220 / LCA — which promotes dephosphorylation of an inhibitory tyrosine of LCK in the cSMAC of memory but not naive T cells. CD45 is also constitutively associated with TCRs in lipid rafts in memory T cells only. However, although LCK activity is prolonged in memory T cells, this does not affect the downstream kinase ZAP70 : prolonged LCK activity might induce alternative memory-cell-specific signalling^ref. The T_h2 immunodominance of the immune response established during a chronic infection (eg Mycobacterium bovis bacille Calmette-Guerin (BCG) infection^ref), which most likely reflects regulatory mechanisms to allow the return to T cell homeostasis, does not shape the T_h1/T_h2 nature of the memory response

obliged signals (if absent => clonal anergy; if present withour TcR-MHC binding => no T-cell activation occurs) :

CD134 / OX40 --- CD134L / OX40L / gp34 (on activated B cells) => up-regulation of Bcl-2and Bcl-x_L.

CD8⁺ memory T cells activation : CD4⁺ T lymphocyte help is not necessary.

facultative (increased survival) signals :

CD137 / 4-1BB (on activated T cells, activated NK cells, monocytes and DCs) --- CD137L / 4-1BBL (carcinoma cell lines) : 4-1BB-mediated NF-kB activation increases expression of the antiapoptotic genes Bcl-x_L and Bcl-2A1 / Bfl-1 ; in contrast, cross-linking of CD137L induces apoptosis in resting lymphocytes.
NKG2D-S and NKG2D-L (via DAP10 but not p14^{DAP12
/ KARAP}) --- MIC proteins

Immune interference occurs by ...

T cell antagonism occurs when an existing memory T cell is functionally inactivated by exposure to a point mutant of its cognate epitope presented on the same MHC I but without inducing TcR activation (altered peptide ligand (APL))
original antigenic sin (OAS) / clonal imprinting describes a phenomenon determined by exposure to previously existing strains in which response elicited in an individual after a secondary viral infection with a novel strain is directly mainly against immunodominant highly cross-reacting (HCR) epitopes at the expense of responses to novel protective epitopes, indirectly favouring severity of the current infection

neutralizing antibodies (NAbs) produced by memory B cells^ref1,
ref2 (not for pneumococcal capsular polysaccharide serotype 6B^ref, SHIV^ref, ...)
memory T helper cells^ref
memory CTLs^ref

^ref

^ref

^ref

influenzaviruses A, B and C

^{ref1
(first OAS report), ref2,
ref3,
ref4,
ref5}

^ref1,
ref2